Bace1 inhibitors

ABSTRACT

The present invention provides a compound of formula I, having BACE1 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer&#39;s disease.

BACKGROUND ART

Alzheimer's disease (AD) is a neurodegenerative disorder of the centralnervous system and the leading cause of a progressive dementia in theelderly population. Its clinical symptoms are impairment of memory,cognition, temporal and local orientation, judgment and reasoning butalso severe emotional disturbances. There are currently no treatmentsavailable which can prevent the disease or its progression or stablyreverse its clinical symptoms. AD has become a major health problem inall societies with high life expectancies and also a significanteconomic burden for their health systems.

AD is characterized by 2 major pathologies in the central nervous system(CNS), the occurrence of amyloid plaques and neurofibrillar tangles(Hardy et al., The amyloid hypothesis of Alzheimer's disease: progressand problems on the road to therapeutics, Science. 2002 Jul. 19;297(5580):353-6, Selkoe, Cell biology of the amyloid beta-proteinprecursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol.1994; 10:373-403). Both pathologies are also commonly observed inpatients with Down's syndrome (trisomy 21), which also develop AD-likesymptoms in early life. Neurofibrillar tangles are intracellularaggregates of the microtubule-associated protein tau (MAPT). Amyloidplaques occur in the extracellular space; their principal components areAβ-peptides. The latter are a group of proteolytic fragments derivedfrom the β-amyloid precursor protein (APP) by a series of proteolyticcleavage steps. Several forms of APP have been identified of which themost abundant are proteins of 695, 751 and 770 amino acids length. Theyall arise from a single gene through differential splicing. TheAβ-peptides are derived from the same domain of the APP but differ attheir N- and C-termini, the main species are of 40 and 42 amino-acidlength. There are several lines of evidence which strongly suggest thataggregated Aβ-peptides are the essential molecules in the pathogenesisof AD: 1) amyloid plaques formed of Aβ-peptides are invariably part ofthe AD pathology; 2) Aβ-peptides are toxic for neurons; 3) in FamilialAlzheimer's Disease (FAD) the mutations in the disease genes APP, PSN1,PSN2 lead to increased levels of Aβ-peptides and early brainamyloidosis; 4) transgenic mice which express such FAD genes develop apathology which bears many resemblances to the human disease.Aβ-peptides are produced from APP through the sequential action of 2proteolytic enzymes termed β- and γ-secretase. β-Secretase cleaves firstin the extracellular domain of APP approximately 28 amino acids outsideof the trans-membrane domain (TM) to produce a C-terminal fragment ofAPP containing the TM- and the cytoplasmatic domain (CTFβ). CTFβ is thesubstrate for γ-secretase which cleaves at several adjacent positionswithin the TM to produce the Aβ peptides and the cytoplasmic fragment.The γ-secretase is a complex of at least 4 different proteins, itscatalytic subunit is very likely a presenilin protein (PSEN1, PSEN2).The β-secretase (BACE1, Asp2; BACE stands for β-site APP-cleavingenzyme) is an aspartyl protease which is anchored into the membrane by atransmembrane domain (Vassar et al., Beta-secretase cleavage ofAlzheimer's amyloid precursor protein by the transmembrane asparticprotease BACE, Science. 1999 Oct. 22; 286(5440): 735). It is expressedin many tissues of the human organism but its level is especially highin the CNS. Genetic ablation of the BACE1 gene in mice has clearly shownthat its activity is essential for the processing of APP which leads tothe generation of Aβ-peptides, in the absence of BACE1 no Aβ-peptidesare produced (Luo et al., Mice deficient in BACE1, the Alzheimer'sbeta-secretase, have normal phenotype and abolished beta-amyloidgeneration, Nat Neurosci. 2001 March; 4(3):231-2, Roberds et al., BACEknockout mice are healthy despite lacking the primary beta-secretaseactivity in brain: implications for Alzheimer's disease therapeutics,Hum Mol Genet. 2001 Jun. 1; 10(12):1317-24). Mice which have beengenetically engineered to express the human APP gene and which formextensive amyloid plaques and Alzheimer's disease like pathologiesduring aging fail to do so when β-secretase activity is reduced bygenetic ablation of one of the BACE1 alleles (McConlogue et al., Partialreduction of BACE1 has dramatic effects on Alzheimer plaque and synapticpathology in APP Transgenic Mice. J Biol Chem. 2007 Sep. 7;282(36):26326). It is thus presumed that inhibitors of BACE1 activitycan be useful agents for therapeutic intervention in Alzheimer's disease(AD). Several patent applications have been filed describing BACE 1inhibitors of various structures, e.g. WO2009103626, WO2010128058,WO2011020806, WO2011029803, WO2011069934, WO2011070029, WO2011138293,WO2012019966, WO2012028563, WO2012098064, WO2012104263, WO2012107371,WO2012110459, WO2012119883, WO2012126791, WO2012136603, WO2012139993,WO2012156284, WO2012163790, WO2012168164, WO2012168175, WO2013004676,WO2013041499, WO2013110622, WO2013174781, WO2014001228, WO2014114532,WO2014150331, WO2014150340 and WO2014150344. Further, WO2012139425 andWO2013028670 describe certain iminothiazines as BACE1 inhibitors.

Furthermore, the formation, or formation and deposition, of β-amyloidpeptides in, on or around neurological tissue (e.g., the brain) areinhibited by the present compounds, i.e. inhibition of the Aβ-productionfrom APP or an APP fragment.

The present invention provides novel compounds of formula I, theirmanufacture, medicaments based on a compound in accordance with theinvention and their production as well as the use of compounds offormula I in the control or prevention of illnesses such as Alzheimer'sdisease.

FIELD OF THE INVENTION

The present invention provides 1-methylimino-1-oxo-2H-1,4-thiazin-amineshaving BACE1 inhibitory properties, their manufacture, pharmaceuticalcompositions containing them and their use as therapeutically activesubstances.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula 1,

wherein the substituents and variables are as described below and in theclaims, or a pharmaceutically acceptable salt thereof.

The present compounds have Asp2 (β-secretase, BACE1 or Memapsin-2)inhibitory activity and may therefore be used in the therapeutic and/orprophylactic treatment of diseases and disorders characterized byelevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloidplaques and further deposits, particularly Alzheimer's disease.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a compound of formula I and theirpharmaceutically acceptable salts thereof, the preparation of the abovementioned compounds, medicaments containing them and their manufactureas well as the use of the above mentioned compounds in the therapeuticand/or prophylactic treatment of diseases and disorders which areassociated with inhibition of BACE1, such as Alzheimer's disease.Furthermore, the formation, or formation and deposition, of β-amyloidplaques in, on or around neurological tissue (e.g., the brain) areinhibited by the present compounds by inhibiting the Aβ production fromAPP or an APP fragment.

The following definitions of the general terms used in the presentdescription apply irrespectively of whether the terms in question appearalone or in combination with other groups.

Unless otherwise stated, the following terms used in this Application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralreferents unless the context clearly dictates otherwise.

The term “C₁₋₆-alkyl”, alone or in combination with other groups, standsfor a hydrocarbon radical which may be linear or branched, with singleor multiple branching, wherein the alkyl group in general comprises 1 to6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl, isopropyl(i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl(tert-butyl), isopentyl, 2-ethyl-propyl (2-methyl-propyl),1,2-dimethyl-propyl and the like. Particular “C₁₋₆-alkyl” are“C₁₋₃-alkyl”. Specific groups are methyl and ethyl. Most specific groupis methyl. The term “halogen-C₁₋₆-alkyl” or “C₁₋₆-alkyl-halogen”, aloneor in combination with other groups, refers to C₁₋₆-alkyl as definedherein, which is substituted by one or multiple halogen, particularly1-5 halogen, more particularly 1-3 halogen. Particular halogen isfluoro. Particular “halogen-C₁₋₆-alkyl” is fluoro-C₁₋₆-alkyl and aparticular “halogen-C₁₋₃-alkyl” is fluoro-C₁₋₃-alkyl. Examples aretrifluoromethyl, difluoromethyl, fluoromethyl and the like. A specificgroup is fluoromethyl.

The term “cyano”, alone or in combination with other groups, refers toN≡C—(NC—).

The term “halogen”, alone or in combination with other groups, denoteschloro (Cl), iodo (I), fluoro (F) and bromo (Br). Particular “halogen”are Cl, I and F. A specific group is F.

The term “heteroaryl”, alone or in combination with other groups, refersto an aromatic carbocyclic group of having a single 4 to 8 memberedring, in particular 5 to 8, or multiple condensed rings comprising 6 to14, in particular 6 to 10 ring atoms and containing 1, 2 or 3heteroatoms individually selected from N, O and S, in particular 1N or2N, in which group at least one heterocyclic ring is aromatic. Examplesof “heteroaryl” include benzofuryl, benzoimidazolyl, 1H-benzoimidazolyl,benzooxazinyl, benzoxazolyl, benzothiazinyl, benzothiazolyl,benzothienyl, benzotriazolyl, furyl, imidazolyl, indazolyl,1H-indazolyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl,oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), 1H-pyrazolyl,pyrazolo[1,5-a]pyridinyl, pyridazinyl, pyridinyl (pyridyl), pyrimidinyl(pyrimidyl), pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl,triazolyl, and the like. Particular “heteroaryl” groups are pyridyl,pyrazinyl and imidazo[1,2-a]pyridinyl. Examples of“5-membered-heteroaryl groups” include triazolyl, thienyl, furyl,imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazolyl (pyrazyl),1H-pyrazolyl, pyrrolyl, tetrazolyl, thiazolyl, triazolyl and the like.Particular “5-membered-heteroaryl groups” are isoxazolyl and triazolyl.Specific “5-membered-heteroaryl groups” are isoxazol-5-yl,isoxazol-3-yl, triazol-1-yl and triazol-4-yl. Examples of“6-membered-heteroaryl groups” include pyrazinyl, pyridazinyl, pyridinyland pyrimidinyl. Particular “6-membered-heteroaryl groups” arepyrazinyl, pyridinyl and pyrimidinyl. Specific “6-membered-heteroarylgroups” are pyrazin-2-yl, pyridin-2-yl and pyrimidin-2-yl.

The term “pharmaceutically acceptable salts” refers to salts that aresuitable for use in contact with the tissues of humans and animals.Examples of suitable salts with inorganic and organic acids are, but arenot limited to acetic acid, citric acid, formic acid, fumaric acid,hydrochloric acid, lactic acid, maleic acid, malic acid,methane-sulfonic acid, nitric acid, phosphoric acid, p-toluenesulphonicacid, succinic acid, sulfuric acid (sulphuric acid), tartaric acid,trifluoroacetic acid and the like. Particular acids are formic acid,trifluoroacetic acid and hydrochloric acid. A specific acid istrifluoroacetic acid.

The term “amino”, alone or in combination with other groups, refers to—NH₂.

The terms “hydroxyl” or “hydroxyl”, alone or in combination with othergroups, refer to —OH.

The term “C₂₋₆-alkynyl-C₁₋₆-alkoxy”, alone or in combination with othergroups, refers to C₁₋₆-alkoxy as defined herein, which is substituted byone or multiple C₂₋₆-alkynyl as defined herein, in particular 1C₂₋₆-alkynyl.

The term “C₂₋₆-alkynyl”, alone or in combination with other groups,denotes a monovalent linear or branched saturated hydrocarbon group of 2to 6 carbon atoms, in particular from 2 to 4 carbon atoms, andcomprising one, two or three triple bonds. Examples of C₂₋₆-alkynylinclude ethynyl, propynyl, and n-butynyl.

The term “C₁₋₆-alkoxy-C₁₋₆-alkyl”, alone or in combination with othergroups, refers to C₁₋₆-alkyl as defined herein, which is substituted byone or multiple C₁₋₆-alkoxy, as defined herein, particularly 1C₁₋₆-alkoxy. Particular “C₁₋₆-alkoxy-C₁₋₆-alkyl” is methoxy-C₁₋₆-alkyl.Examples are methoxymethyl, methoxyethyl and the like.

The term “C₁₋₆-alkoxy”, alone or in combination with other groups,stands for an —O—C₁₋₆-alkyl radical which may be linear or branched,with single or multiple branching, wherein the alkyl group in generalcomprises 1 to 6 carbon atoms, for example, methoxy (OMe, MeO), ethoxy(OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (iso-butoxy),2-butoxy (sec-butoxy), t-butoxy (tert-butoxy), isopentyloxy(i-pentyloxy) and the like. Particular “C₁₋₆-alkoxy” are groups with 1to 4 carbon atoms. Specific are ethoxy and methoxy.

The term “halogen-C₁₋₆-alkoxy”, alone or in combination with othergroups, refers to C₁₋₆-alkoxy as defined herein, which is substituted byone or multiple halogens, in particular fluoro. Particular“halogen-C₁₋₆-alkoxy” are fluoro-C₁₋₆-alkoxy. Specific“halogen-C₁₋₆-alkoxy” are CHF₂—CF₂—CH₂—O—, CHF₂—O— and CF₂—O—.

The terms “pharmaceutically acceptable carrier” and “pharmaceuticallyacceptable auxiliary substance” refer to carriers and auxiliarysubstances such as diluents or excipients that are compatible with theother ingredients of the formulation.

The term “pharmaceutical composition” encompasses a product comprisingspecified ingredients in pre-determined amounts or proportions, as wellas any product that results, directly or indirectly, from combiningspecified ingredients in specified amounts. Particularly it encompassesa product comprising one or more active ingredients, and an optionalcarrier comprising inert ingredients, as well as any product thatresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients.

The term “inhibitor” denotes a compound which competes with, reduces orprevents the binding of a particular ligand to particular receptor orwhich reduces or prevents the inhibition of the function of a particularprotein.

The term “half maximal inhibitory concentration” (IC₅₀) denotes theconcentration of a particular compound required for obtaining 50%inhibition of a biological process in vitro. IC₅₀ values can beconverted logarithmically to pIC₅₀ values (−log IC₅₀), in which highervalues indicate exponentially greater potency. The IC₅₀ value is not anabsolute value but depends on experimental conditions e.g.concentrations employed. The IC₅₀ value can be converted to an absoluteinhibition constant (Ki) using the Cheng-Prusoff equation (Biochem.Pharmacol. (1973) 22:3099). The term “inhibition constant” (Ki) denotesthe absolute binding affinity of a particular inhibitor to a receptor.It is measured using competition binding assays and is equal to theconcentration where the particular inhibitor would occupy 50% of thereceptors if no competing ligand (e.g. a radioligand) was present. Kivalues can be converted logarithmically to pKi values (−log Ki), inwhich higher values indicate exponentially greater potency.

“Therapeutically effective amount” means an amount of a compound that,when administered to a subject for treating a disease state, issufficient to effect such treatment for the disease state. The“therapeutically effective amount” will vary depending on the compound,disease state being treated, the severity or the disease treated, theage and relative health of the subject, the route and form ofadministration, the judgment of the attending medical or veterinarypractitioner, and other factors.

The term “as defined herein” and “as described herein” when referring toa variable incorporates by reference the broad definition of thevariable as well as particularly, more particularly and mostparticularly definitions, if any.

The terms “treating”, “contacting” and “reacting” when referring to achemical reaction means adding or mixing two or more reagents underappropriate conditions to produce the indicated and/or the desiredproduct. It should be appreciated that the reaction which produces theindicated and/or the desired product may not necessarily result directlyfrom the combination of two reagents which were initially added, i.e.,there may be one or more intermediates which are produced in the mixturewhich ultimately leads to the formation of the indicated and/or thedesired product.

The term “aromatic” denotes the conventional idea of aromaticity asdefined in the literature, in particular in IUPAC—Compendium of ChemicalTerminology, 2nd, A. D. McNaught and A. Wilkinson (Eds). BlackwellScientific Publications, Oxford (1997).

The term “pharmaceutically acceptable excipient” denotes any ingredienthaving no therapeutic activity and being non-toxic such asdisintegrators, binders, fillers, solvents, buffers, tonicity agents,stabilizers, antioxidants, surfactants or lubricants used in formulatingpharmaceutical products.

Whenever a chiral carbon is present in a chemical structure, it isintended that all stereoisomers associated with that chiral carbon areencompassed by the structure as pure stereoisomers as well as mixturesthereof.

The invention also provides pharmaceutical compositions, methods ofusing, and methods of preparing the aforementioned compounds.

All separate embodiments may be combined.

One embodiment of the invention provides a compound of formula I,

A is a heteroaryl group,B is a heteroaryl group,R¹ is selected from the group consisting of

-   -   i) C₁₋₆-alkyl and    -   ii) halogen-C₁₋₆-alkyl;        R² is selected from the group consisting of    -   i) C₁₋₆-alkyl, and    -   ii) halogen-C₁₋₆-alkyl;        or R¹ and R² form together with the C-atom they are attached to,        a C₃₋₆-cycloalkyl-, wherein the C₃₋₆-cycloalkyl- is optionally        substituted by one or more substituents selected from the group        consisting of halogen and hydroxyl;        R³ is selected from the group consisting of    -   i) hydrogen,    -   ii) C₃₋₆-cycloalkyl,    -   iii) halogen-C₁₋₆-alkyl, and    -   iv) C₁₋₆-alkyl;        R⁴ is selected from the group consisting of    -   i) hydrogen, and    -   ii) C₁₋₆-alkyl;        R⁵ is selected from the group consisting of    -   i) C₁₋₆-alkyl, and    -   ii) halogen-C₁₋₆-alkyl;        R⁶ is halogen;        R⁷ is selected from the group consisting of    -   i) amino,    -   ii) cyano,    -   iii) hydrogen,    -   iv) OH,    -   v) halogen,    -   vi) C₁₋₆-alkyl,    -   vii) C₁₋₆-alkyl-C₃₋₆-cycloalkyl,    -   viii) halogen-C₁₋₆-alkyl,    -   ix) C₁₋₆-alkoxy-C₁₋₆-alkyl,    -   x) C₂₋₆-alkynyl,    -   xi) C₂₋₆-alkynyl-C₁₋₆-alkyl,    -   xii) C₂₋₆-alkynyl-C₁₋₆-alkoxy    -   xiii) C₁₋₆-alkoxy, and    -   xiv) halogen-C₁₋₆-alkoxy;        or pharmaceutically acceptable salts thereof.

A certain embodiment of the invention provides a compound of formula I,wherein

A is a heteroaryl group,B is a heteroaryl group,R¹ is selected from the group consisting of

-   -   i) C₁₋₆-alkyl and    -   ii) halogen-C₁₋₆-alkyl;        R² is selected from the group consisting of    -   i) C₁₋₆-alkyl, and    -   ii) halogen-C₁₋₆-alkyl;        or R¹ and R² form together with the C-atom they are attached to,        a C₃₋₆-cycloalkyl-, wherein the C₃₋₆-cycloalkyl- is optionally        substituted by one or more substituents selected from the group        consisting of halogen and hydroxyl;        R³ is selected from the group consisting of    -   i) hydrogen,    -   ii) halogen-C₁₋₆-alkyl, and    -   iii) C₁₋₆-alkyl;        R⁴ is selected from the group consisting of    -   i) hydrogen, and    -   ii) C₁₋₆-alkyl;        R⁵ is selected from the group consisting of    -   i) C₁₋₆-alkyl, and    -   ii) halogen-C₁₋₆-alkyl;        R⁶ is halogen;        R⁷ is selected from the group consisting of    -   i) amino,    -   ii) cyano,    -   iii) hydrogen,    -   iv) halogen,    -   v) C₁₋₆-alkyl,    -   vi) halogen-C₁₋₆-alkyl,    -   vii) C₁₋₆-alkoxy-C₁₋₆-alkyl,    -   viii) C₂₋₆-alkynyl,    -   ix) C₂₋₆-alkynyl-C₁₋₆-alkyl,    -   x) C₂₋₆-alkynyl-C₁₋₆-alkoxy    -   xi) C₁₋₆-alkoxy, and    -   xii) halogen-C₁₋₆-alkoxy;        or pharmaceutically acceptable salts thereof.

A certain embodiment of the invention provides a compound of formula I,which is of formula Ia, wherein A, B, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ areas defined herein

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein A is a 5-membered heteroaryl group.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein A is isoxazolyl or triazolyl.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein B is a 6-membered heteroaryl group.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein B is pyrimidinyl, pyrazinyl or pyridinyl.

A certain embodiment of the invention provides a compound of formula Tas described herein, wherein R¹ is C₁₋₆-alkyl.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R¹ is methyl.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R² is C₁₋₆-alkyl.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R² is methyl.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R¹ and R² form together with the C-atomthey are attached to a C₃₋₆-cycloalkyl-.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R¹ and R² form together with the C-atomthey are attached to a cyclopentyl.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R³ is C₁₋₆-alkyl.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R³ is methyl.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R³ is H, CH₃, CD₃, CH₂CF₃ or cyclopropyl.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R⁴ is hydrogen.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R⁵ is C₁₋₆-alkyl or halogen-C₁₋₆-alkyl.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R⁵ is methyl or —CH₂F.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R⁵ is methyl.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R⁵ is-CH₂F.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R⁶ is F.

A certain embodiment of the invention provides a compound of formula Tas described herein, wherein R⁷ is Br, CH₂-cyclopropyl, Cl, CN, Et, Me,OCH₂CF₂CHF₂, OCH₂CF₃, OCH₂CHF₂, OH or OMe.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R⁷ is selected from the group consisting ofcyano, halogen, C₁₋₆-alkoxy and halogen-C₁₋₆-alkoxy.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein R⁷ is selected from the group consisting ofchloro, cyano, methoxy and 2,2-difluoroethoxy.

A certain embodiment of the invention provides a compound of formula Tas described herein, wherein A is a 5-membered heteroaryl group, B is a6-membered heteroaryl group, R¹ is methyl, R² is methyl, R³ is methyl,R⁴ is hydrogen, R⁵ is methyl or —CH₂F, R⁶ is F and R⁷ is selected fromthe group consisting of cyano, halogen, C₁₋₆-alkoxy andhalogen-C₁₋₆-alkoxy.

A certain embodiment of the invention provides a compound of formula Ias described herein, wherein A is selected from the group consisting ofisoxazolyl and triazolyl, B is selected from the group consisting ofpyrimidinyl, pyrazinyl and pyridinyl, R¹ is methyl, R² is methyl, R³ ismethyl, R⁴ is hydrogen, R⁵ is methyl or —CH₂F, R⁶ is F and R⁷ isselected from the group consisting of cyano, halogen, C₁₋₆-alkoxy andhalogen-C₁₋₆-alkoxy.

A certain embodiment of the invention provides a compound of formula Ias described herein that is selected from the group consisting of

-   (1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;    2,2,2-trifluoroacetic acid,-   (1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine    2,2,2-trifluoroacetate,-   (1R,3R)-3-[2-fluoro-5-[3-[5-(2,2,3,3-tetrafluoropropoxy)pyrimidin-2-yl]isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine    2,2,2-trifluoroacetate,-   (1R,3R)-3-[5-[1-(5-chloro-2-pyridyl)triazol-4-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;    2,2,2-trifluoroacetic acid,-   (1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;    2,2,2-trifluoroacetic acid,-   (1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-1-cyclopropylimino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine    2,2,2-trifluoroacetate,-   (1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine;    2,2,2-trifluoroacetic acid 2,2,2-trifluoroacetate,-   (1R,3R)-3-[5-[3-(5-ethylpyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine    2,2,2-trifluoroacetate,-   (1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrazin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;    2,2,2-trifluoroacetic acid,-   (1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine,-   (1R,3R)-5-amino-1-(cyclopropylimino)-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine    1-oxide,-   (1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-hydroxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide,-   (1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-1-imino-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine    1-oxide,-   (1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide,-   (1R,3R)-5-amino-3-(5-(3-(5-(cyclopropylmethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide,-   (1R,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1R,3S)-3-[2-fluoro-5-[3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl]phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine,-   (1R,3S)-5-amino-3-(5-(1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1R,3S)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1R,3S)-5-amino-3-(5-(3-(5-bromo-3-methylpyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1R,3S)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1S,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine    2,2,2-trifluoroacetate,-   (1S,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine    2,2,2-trifluoroacetate,-   (1S,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine,-   (1S,3R)-5-amino-1-(cyclopropylimino)-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1S,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1S,3R)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-(cyclopropylimino)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine    1-oxide 2,2,2-trifluoroacetate,-   (1S,3S)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;    2,2,2-trifluoroacetic acid,-   (1S,3S)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;    2,2,2-trifluoroacetic acid,-   (1S,3S)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide,-   (6R,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene    6-oxide 2,2,2-trifluoroacetate,-   (6R,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene    6-oxide 2,2,2-trifluoroacetate,-   (6R,8R)-10-amino-8-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene    6-oxide,-   (6R,8R)-10-amino-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene    6-oxide 2,2,2-trifluoroacetate,-   (6S,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene    6-oxide 2,2,2-trifluoroacetate,-   (6S,8R)-10-amino-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene    6-oxide 2,2,2-trifluoroacetate,-   2-[5-[3-[(1R,3R)-5-amino-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-3-yl]-4-fluoro-phenyl]isoxazol-3-yl]pyrimidine-5-carbonitrile;    2,2,2-trifluoroacetic acid,-   6-(4-(3-((1R,3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-1-oxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile    2,2,2-trifluoroacetate,    and-   6-[4-[3-[(1R,3R)-5-amino-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-3-yl]-4-fluoro-phenyl]triazol-1-yl]pyridine-3-carbonitrile    2,2,2-trifluoroacetic acid.

A certain embodiment of the invention provides a compound of formula Ias described herein that is selected from the group consisting of

-   (1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine    trifluoroacetate,-   (1R,3R)-3-[5-[1-(5-chloro-2-pyridyl)triazol-4-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine    trifluoroacetate,-   (1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine    trifluoroacetate,-   (1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrazin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine    trifluoroacetate,-   (1R,3S)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide trifluoroacetate,-   (1R,3S)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide trifluoroacetate,-   (1S,3R)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide trifluoroacetate,-   (1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine    1-oxide trifluoroacetate,-   (1S,3S)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine    trifluoroacetate,-   (1S,3S)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine    trifluoroacetate,-   2-[5-[3-[(1R,3R)-5-amino-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-3-yl]-4-fluoro-phenyl]isoxazol-3-yl]pyrimidine-5-carbonitrile    trifluoroacetate, and-   6-[4-[3-[(1R,3R)-5-amino-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-3-yl]-4-fluoro-phenyl]triazol-1-yl]pyridine-3-carbonitrile    trifluoroacetate.

A certain embodiment of the invention provides a compound of formula Tas described herein that is selected from the group consisting of

-   (1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrazin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;    2,2,2-trifluoroacetic acid-   (1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;    2,2,2-trifluoroacetic acid-   (1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;    2,2,2-trifluoroacetic acid and-   (1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine    2,2,2-trifluoroacetate.

A certain embodiment of the invention provides a compound of formula Ias described herein that is selected from the group consisting of

-   (1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrazin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine    trifluoroacetate,-   (1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine    trifluoroacetate, and-   (1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine    trifluoroacetate.

A certain embodiment of the invention provides a compound of formula Ias described herein that is(1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-aminetrifluoroacetate.

A certain embodiment of the invention provides a compound of formula Ias described herein whenever prepared by a process as described herein.

A certain embodiment of the invention provides a compound of formula Ias described herein for use as therapeutically active substance.

A certain embodiment of the invention provides a compound of formula Ias described herein for the use as inhibitor of BACE1 activity.

A certain embodiment of the invention provides a compound of formula Ias described herein for the use as therapeutically active substance forthe therapeutic and/or prophylactic treatment of diseases and disorderscharacterized by elevated β-amyloid levels and/or β-amyloid oligomersand/or β-amyloid plaques and further deposits or Alzheimer's disease.

A certain embodiment of the invention provides a compound of formula Ias described herein for the use as therapeutically active substance forthe therapeutic and/or prophylactic treatment of Alzheimer's disease.

A certain embodiment of the invention provides a pharmaceuticalcomposition comprising a compound of formula I as described herein and apharmaceutically acceptable carrier and/or a pharmaceutically acceptableauxiliary substance.

A certain embodiment of the invention provides the use of a compound offormula I as described herein for the manufacture of a medicament forthe use in inhibition of BACE1 activity.

A certain embodiment of the invention provides the use of a compound offormula I as described herein for the manufacture of a medicament forthe therapeutic and/or prophylactic treatment of diseases and disorderscharacterized by elevated β-amyloid levels and/or β-amyloid oligomersand/or β-amyloid plaques and further deposits or Alzheimer's disease.

A certain embodiment of the invention provides the use of a compound offormula I as described herein for the manufacture of a medicament forthe therapeutic and/or prophylactic treatment of Alzheimer's disease.

A certain embodiment of the invention provides the use of a compound offormula I as described herein for the manufacture of a medicament forthe therapeutic and/or prophylactic treatment of Alzheimer's disease.

A certain embodiment of the invention provides a compound of formula Ias described herein for the use in inhibition of BACE1 activity.

A certain embodiment of the invention provides a compound of formula Tas described herein for the use in the therapeutic and/or prophylactictreatment of diseases and disorders characterized by elevated β-amyloidlevels and/or β-amyloid oligomers and/or β-amyloid plaques and furtherdeposits or Alzheimer's disease.

A certain embodiment of the invention provides a compound of formula Ias described herein for the use in the therapeutic and/or prophylactictreatment of Alzheimer's disease.

A certain embodiment of the invention provides a method for the use ininhibition of BACE1 activity, particularly for the therapeutic and/orprophylactic treatment of diseases and disorders characterized byelevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloidplaques and further deposits or Alzheimer's disease, which methodcomprises administering compound of formula I as described herein to ahuman being or animal.

A certain embodiment of the invention provides a method for the use inthe therapeutic and/or prophylactic treatment of Alzheimer's disease,which method comprises administering a compound of formula I asdescribed herein to a human being or animal.

Furthermore, the invention includes all optical isomers, i.e.diastereoisomers, diastereomeric mixtures, racemic mixtures, all theircorresponding enantiomers and/or tautomers as well as their solvates ofthe compounds of formula I.

The invention also includes various deuterated forms of compounds offormula I or pharmaceutically acceptable salts thereof. Each availablehydrogen atom attached to a carbon atom may be independently replacedwith a deuterium atom, in particular a CH₃ group may be replaced by aCD₃ group. A skilled person will know how to synthesize deuterated formsof compounds of formula I or pharmaceutically acceptable salts thereof.

The skilled person in the art will recognize that the compounds offormula I can exist in tautomeric form

All tautomeric forms are encompassed in the present invention.

The compounds of formula I may contain one or more asymmetric centersand can therefore occur as racemates, racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers.Additional asymmetric centers may be present depending upon the natureof the various substituents on the molecule. Each such asymmetric centerwill independently produce two optical isomers and it is intended thatall of the possible optical isomers and diastereomers in mixtures and aspure or partially purified compounds are included within this invention.The present invention is meant to encompass all such isomeric forms ofthese compounds. The independent syntheses of these diastereomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography.

Certain embodiments are the following specific forms:

In the embodiments, where optically pure enantiomers are provided,optically pure enantiomer means that the compound contains >90% of thedesired isomer by weight, particularly >95% of the desired isomer byweight, or more particularly >99% of the desired isomer by weight, saidweight percent based upon the total weight of the isomer(s) of thecompound. Chirally pure or chirally enriched compounds may be preparedby chirally selective synthesis or by separation of enantiomers. Theseparation of enantiomers may be carried out on the final product oralternatively on a suitable intermediate.

The synthesis of compounds of formula (I) is illustrated in Scheme 1.

Starting materials (II) are known or can be prepared in analogy to knownmethods (e.g. described in Bioorg. Med. Chem. Lett. 2013, 23,4239-4243). Starting materials (III) are known or can be prepared inanalogy to known methods (e.g. described in WO2014/150331). Startingmaterial (II) can be reacted with sulfoximine (III) in the presence of astrong base, e.g. alkali hexamethyldisilazide, such as lithiumhexamethyldisilazide, alkali diisopropylamide, such as lithiumdiisopropylamide, or alkyl lithium, such as n-butyl lithium, underanhydrous conditions in a suitable aprotic solvent, e.g. tetrahydrofuranor dichloromethane, to form (IV) as a mixture of stereoisomers. Thesingle stereoisomers can be separated at this or at a later stage bychromatography and the route depicted in Scheme 1 can be followedanalogously employing the separated single isomers.

The sulfinamide moiety of (IV) can be cleaved with a mineral acid, e.g.sulfuric acid or particularly hydrochloric acid, in a solvent such as anether, e.g. diethyl ether, tetrahydrofuran or more particularly1,4-dioxane to give the corresponding amine (V). Subsequently, (V) canbe cyclised to amidines (VI) using methods known in the art, e.g. usingstoichiometric amounts of copper(I) salts, e.g. copper(I) chloride orcopper(I) bromide, in suitable solvents, e.g. alcohols, such as ethanol,at elevated temperatures, such as 20° C. to 130° C., preferably at 70°C. to 90° C. Alternatively, the transformation can be achieved usingstoichiometric amounts of a Lewis acid, like trimethyl aluminium, in asuitable aprotic solvent, such as toluene.

Compounds (VI) can be converted into compounds (VII) containing aleaving group such as iodide or bromide by e.g. iodination using aniodinating agent such as N-iodosuccinimide in the presence of an acidsuch as trifluoromethanesulfonic acid or tetrafluoroboric acid in asolvent such as dichloromethane at a temperature between 0° C. andreflux temperature of the solvent or by bromination using a brominatingagent such as N-bromosuccinimide in the presence of an acid or acidmixtures such as trifluoroacetic acid and sulfuric acid. Protection ofthe amino group in compounds of formula (VII) to produce compounds offormula (VIII) can be performed by methods known in the art, e.g. asdescribed in T. W. Greene and P. G. M. Wuts, “Protective Groups inOrganic Synthesis”, 2nd ed., John Wiley & Sons, Inc., New York, N.Y.,1991. In case PG is tert-butoxycarbonyl (BOC), the transformation can beachieved by treatment with di-tert-butyl dicarbonate in a solvent suchas dichloromethane at temperatures between between 0° C. and refluxtemperature of the solvent. In case PG is a triarylmethyl, thetransformation can be achieved by treatment with triarylmethylchlorides, such as triphenylmethyl chloride (Tr-Cl),di(p-methoxyphenyl)phenylmethyl chloride (DMTr-Cl) under basicconditions, e.g. in the presence of an amine, such as triethylamine ordiisopropylethylamine, in a chlorinated solvent, such as dichloromethaneor chloroform, at temperatures between 0° C. and ambient temperature.

Sonogashira coupling of terminal alkynes (IX) with compounds of formula(VIII) in which LG is preferably iodide to yield compounds of formula(X) can be achieved with a palladium catalyst, e.g.bis(triphenyphosphine)palladium(II) chloride, a copper(I) co-catalyst,e.g. copper(I) iodide, and an amine base, e.g. triethylamine underconditions known to those skilled in the art.

Removal of the R₃Si group of compounds (X) to give terminal acetylenes(XI) can be achieved by methods well known in the art, e.g. by treatmentwith fluoride containing reagents such as tetrabutylammonium fluoride ina solvent such as dichloromethane or THF at a temperature between 0° C.and ambient temperature or by treatment with potassium carbonate in asolvent such as ethanol or methanol at ambient temperature.

Conversion of acetylenes (XI) into isoxazoles (XIII) can be achieved bya 1,3-dipolar cycloaddition with a reagent system consisting of aheteroaryl-carboximidoyl chloride (XII) and a base such as sodiumbicarbonate or triethylamine in a solvent such as THF or isopropanol attemperatures between between 0° C. and reflux temperature of thesolvent.

Conversion of acetylenes (XI) into triazoles (XV) can be achieved by acopper(I)-catalyzed cycloaddition with heteroaryl azides (XIV) usingeither a copper(I) reagent such as CuI or copper(I)trifluoromethanesulfonate benzene complex or a copper(II) reagent suchas CuSO4 in the presence of a reducing agent such as sodium ascorbateand a base such as NaHCO₃ in a solvent or solvent mixtures such astoluene, THF or DMF at a temperature from ambient temperature to refluxof the solvent.

Removal of the amine-protecting group PG in compounds (XIII) andcompounds (XV) to give compounds of formula (I) can be achieved bymethods well known in the art, e.g. by treatment with strong carbonicacids, e.g. trifluoroacetic acid, in a solvent, e.g. dichloromethane, attemperatures between 0° C. and 23° C. The product of formula (I) caneither be isolated as a salt, e.g. as a trifluoroacetic acid salt or asa free base. The free base of compounds of formula (I) can be obtainedfrom the corresponding salts by treatment with a base and, if desiredcan be converted into a salt with another acid by treatment with thecorresponding acid.

Heteroaryl-carboximidoyl chlorides (XII) are known or can be prepared inanalogy to methods known in the art or using methods illustrated inScheme 2. Heteroaryl nitriles (XVI) can be converted into heteroarylamidoximes (XVII) by treatment with hydroxylamine or a hydroxylaminesalt such as hydroxylamine hydrochloride in the presence of a base suchas sodium hydroxide or triethylamine in a solvent or solvent mixturessuch as water and ethanol at temperatures between between 0° C. andreflux temperature of the solvent. Conversion of compounds (XVII) intoheteroaryl-carboximidoyl chlorides (XII) can be performed by aSandmeyer-type reaction by treatment with a nitrite such as sodiumnitrite in the presence of aqueous hydrochloric acid preferably at atemperature <10° C.

An alternative synthesis of compounds of formula (I) is depicted inScheme 3: compounds (VIII) containing a leaving group such as I or Brcan be coupled with metal derivatives such as boronic acids or boronicacid esters (XVIII) using well-known cross-coupling reaction conditions.In particular, the coupling of compounds (VIII) with a boronic acid or aboronic ester (XVIII) to the compound of formula (XIX) can be effectedwith a ferrocen derived catalyst, in particular1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride complexwith dichloromethane and a metal carbonate, in particular cesiumcarbonate in a solvent mixture of an ether and water, in particular THFand water at elevated temperature, in particular between 80-90° C.

Removal of the amine-protecting group PG to give compounds of formula(I) can be achieved by methods well known in the art, e.g. by treatmentwith strong carbonic acids, e.g. trifluoroacetic acid, in a solvent,e.g. dichloromethane, at temperatures between 0° C. and 23° C. Theproduct of formula (I) can either be isolated as a salt, e.g. as atrifluoroacetic acid salt or as a free base. The free base of compoundsof formula (I) can be obtained from the corresponding salts by treatmentwith a base and, if desired can be converted into a salt with anotheracid by treatment with the corresponding acid.

The corresponding pharmaceutically acceptable salts with acids can beobtained by standard methods known to the person skilled in the art,e.g. by dissolving the compound of formula I in a suitable solvent suchas e.g. dioxane or tetrahydrofuran and adding an appropriate amount ofthe corresponding acid. The products can usually be isolated byfiltration or by chromatography. The conversion of a compound of formulaI into a pharmaceutically acceptable salt with a base can be carried outby treatment of such a compound with such a base. One possible method toform such a salt is e.g. by addition of 1/n equivalents of a basic saltsuch as e.g. M(OH)_(n), wherein M=metal or ammonium cation and n=numberof hydroxide anions, to a solution of the compound in a suitable solvent(e.g. ethanol, ethanol-water mixture, tetrahydrofuran-water mixture) andto remove the solvent by evaporation or lyophilisation. Particular saltsare hydrochloride, formate and trifluoroacetate. Specific istrifluoroacetate.

Insofar as their preparation is not described in the examples, thecompounds of formula I as well as all intermediate products can beprepared according to analogous methods or according to the methods setforth herein. Starting materials are commercially available, known inthe art or can be prepared by methods known in the art or in analogythereto.

It will be appreciated that the compounds of general formula I in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.

Pharmacological Tests

The compounds of formula I and their pharmaceutically acceptable saltspossess valuable pharmacological properties. It has been found that thecompounds of the present invention are associated with inhibition ofBACE1 activity. The compounds were investigated in accordance with thetest given hereinafter.

Cellular Aβ-Lowering Assay:

The Abeta 40 AlphaLISA Assay can be used. The HEK293 APP cells wereseeded in 96 well Microtiter plates in cell culture medium (Iscove's,plus 10% (v/v) fetal bovine serum, penicillin/streptomycin) to about 80%confluency and the compounds were added at a 3× concentration in 1/3volume of culture medium (final DMSO concentration was kept at 1% v/v).After 18-20 hrs incubation at 37° C. and 5% CO₂ in a humidifiedincubator, the culture supernatants were harvested for the determinationof Aβ 40 concentrations using Perkin-Elmer Human Amyloid beta 1-40 (highspecificity) Kit (Cat # AL275C).

In a Perkin-Elmer White Optiplate-384 (Cat #6007290), 2 μl culturesupernatants were combined with 2 μl of a 10× AlphaLISA Anti-hAβAcceptorbeads+Biotinylated Antibody Anti-Aβ 1-40 Mix (50 μg/mL/5 nM). After 1hour room temperature incubation, 16 μl of a 1.25× preparation ofStreptavidin (SA) Donor beads (25 g/mL) were added and incubated for 30minutes in the Dark. Light Emission at 615 nm was then recorded usingEnVision-Alpha Reader. Levels of Aβ 40 in the culture supernatants werecalculated as percentage of maximum signal (cells treated with 1% DMSOwithout inhibitor). The IC₅₀ values were calculated using the ExcelXLfit software.

Lowering of Aβ40 in Brain of Wild-Type Mice:

Animals and Housing Conditions.

Animals were maintained in a 12/12 h light/dark cycle, with lightsstarting at 6 a.m., and experiments were conducted during the lightphase. Animal housing and experimental procedures were in line withethical and legal guidelines and were authorized by local veterinaryauthorities.

Experiment.

Female C₅₇Bl/6J mice were treated with a dose of 30 mg/kg of thecompounds, 3-4 animals per treatment group. The test compound wasdissolved in 5% EtOH, 10% Solutol, and was applied per os at 10 mL/kg.After 4 h, the animals were sacrificed and brain and plasma werecollected. The brain was cut into halves and immediately frozen on dryice. Brain was used for measurement of Aβ40 and plasma was used fordetermination of compound exposure. The method for Aβ40 determination inbrain lysates followed the known procedure (Lanz, T. A.; Schachter, J.B. Demonstration of a common artifact in immunosorbent assays of brainextracts: development of a solidphase extraction protocol to enablemeasurement of amyloid-β from wild-type rodent brain. J. Neurosci.Methods 2006, 157, 71-81.). Brain tissue was homogenized in 2% DEAbuffer in a Roche MagnaLyser (20″, 4000 rpm) and subsequentlycentrifuged for 1 h at 100000 g. DEA was reduced to 0.2% in 50 mM NaCland one-half of the DEA lysate was passed over an Oasis Solid phaseextraction plate (Waters; cat. no. 186000679), which had been activatedwith MeOH and equilibrated in dH2O (1 mL each). After washes in 10% and30% MeOH (1 mL each), the Aβ-peptides were eluted in 0.8 mL of 2% NH₄OHin 90% MeOH. The eluate was dried over a N2 flow, and the dried samplewas reconstituted in 30 μL of AlphaLISA assay buffer. Aβ40 wasdetermined by an AlphaLISA assay (Perkin-Elmer). In a white 96-well,half area microplate (Perkin-Elmer cat. no. 6005561), 20 μL of thereconstituted sample were mixed with 5 μL of biotinylated BAP-24(specific for C-terminus of Aβ40) (Brockhaus, M.; Grunberg, J.; Rohrig,S.; Loetscher, H.; Wittenburg, N.; Baumeister, R.; Jacobsen, H.; Haass,C. Caspasemediated cleavage is not required for the activity ofpresenilins in amyloidogenesis and NOTCH signaling. NeuroReport 1998, 9,1481-1486.) stock=4.4 mg/mL, f.c.5.5 μg/mL), and 5 μL 252Q6 acceptorbeads (252Q6 antibody, Invitrogen AMB0062) had been previouslyconjugated with AlphaLISA Acceptor beads (Perkin-Elmer cat. no.6772002); final dilution 1:500). The mix was incubated for 1 h at RT inthe dark. Then 20 μL of Streptavin-coated Donor Beads (Perkin-Elmer cat.no. 6760002, final dilution 1:125) were added and this final mix wasincubated in the dark for another 30 min at RT before RFU was measuredin an AlphaScreen Reader (Perkin-Elmer Envision 2104). The valueobtained for Aβ40 in the treated animals was related to the value in thevehicle group and is given in %. Alternatively a commercial ELISA wasused for Aβ40 determination (Wako ELISA: (“Human/Rat β Amyloid (40)ELISA kit Wako II”; cat nr. 294-64701) following the manufacture'sinstruction. Also here the Aβ-lowering efficacy was calculated aspercentage of the vehicle group.

TABLE 1 IC50 values of selected examples BACE1 cell act. Aβ40 IC₅₀Example Structure [nM] 1

95 2

141 3

89 4

111 5

13 6

6 7

56 8

22 9

17 10

20 11

51 12

19 13

106 14

103 15

344 16

156 17

119 18

13 19

27 20

3 21

9 22

61 23

>1000 24

50 25

13 26

37 27

139 28

7 29

20 30

104 31

— 32

— 33

92 34

13 35

13 36

7 37

6 38

13 39

232 40

37 41

8 42

— 43

— 44

—

CYP Inhibition Assay

Inhibition of cytochromes P450 (CYPs) 2C9, 2D6 and 3A4 was assessedusing human liver microsomes and CYP-selective substrate metabolismreactions. 50 μl incubations were made up containing (finally) 0.2 mg/mlpooled human liver microsomes, 5 μM substrate (diclofenac for CYP2C9[4′hydroxylase], dextromethorphan for CYP2D6 [O-demethylase] ormidazolam for CYP3A4 [1′hydroxylase]), 0.25 μL DMSO containing testinhibitor and NADPH regenerating system. Test inhibitor concentrationsof 50, 16.7, 5.6, 1.9, 0.6 and 0.2 μM were assessed in singlicate.Incubations were prewarmed to 37° C. for 10 minutes before initiation byaddition of NADPH regenerating system. Incubations were quenched after 5minutes (20 minutes for dextromethorphan) by addition of 50 μl coldacetonitrile containing 20 ng/ml 4-OH-diclofenac-13C6, 20 ng/mLdextrorphan-D3 and 20 ng/mL 1-OH-midazolam-D4. Quenched incubates werestored at −20° C. for at least 1 hour before centrifugation (20,000×g,20 minutes).

Supernatants were removed and diluted 1:1 with water prior to analysisusing a RapidFire sample injector system and APT4000 mass spectrometer.Peak areas for substrate, metabolite and stable-labelled metabolitestandard were determined using MS/MS. The peak area ratios between themetabolite generated by the enzymatic reaction and the internal standardwere used in subsequent calculations. The percentage of (DMSO) controlactivity was calculated for each incubate and IC₅₀ values estimated bynon-linear regression. Sulfaphenazole, quinidine or ketoconazole weretested in each CYP2C9, CYP2D6 or CYP3A4 inhibition experiment,respectively, to ensure assay sensitivity and reproducibility.(Validated assays for human cytochrome P450 activities, R. L. Walsky andR. S. Obach, Drug Metabolism and Disposition 32: 647-660, 2004, and S.Fowler and H. Zhang, The AAPS Journal, Vol. 10, No. 2, 410-424, 2008)

Cathepsin D and Cathepsin E Fluorescent Substrate Kinetic Assays

General Assay Principle

The MR121 fluorescence assays described below are based on the fact thatMR121 forms a non-fluorescent ground state complex with tryptophan. Insolution this formation occurs at millimolar concentrations oftryptophan. The mechanism can be used to design a generic biochemicalassay for proteases. A substrate peptide is labeled at the N-terminuswith tryptophan and at the C-terminus with the fluorophore MR121 (forcathepsin D the 10 amino acid peptide WTSVLMAAPC-MR121 was used; forcathepsin E, MR121-CKLVFFAEDW was used). In absence of proteaseactivity, the substrates remain intact and the MR121 fluorescence isreduced by the high local Trp-concentration. If the substrates arecleaved by the enzymes the MR121 fluorescence is recovered.

Assay Procedure

The fluorescent substrate cathepsin D and cathepsin E kinetic assayswere performed at room temperature in 384-well microtiter plates (blackwith clear flat bottom, non-binding surface plates from Corning) in afinal volume of 51 μl. The test compounds were serially diluted in DMSO(15 concentrations, 1/3 dilution steps) and 1 μl of diluted compoundswere mixed for 10 min with 40 μl of cathepsin D (from human liver,Calbiochem) diluted in assay buffer (100 mM sodium acetate, 0.05% BSA,pH 5.5; final concentration: 200 nM) or with 40 μl of recombinant humancathepsin E (R&D Systems) diluted in assay buffer (100 mM sodiumacetate, 0.05% BSA, pH 4.5; final concentration: 0.01 nM). Afteraddition of 10 μl of the cathepsin D substrate WTSVLMAAPC-MR121 dilutedin cathepsin D assay buffer (final concentration: 300 nM) or 10 μl ofthe cathepsin E substrate MR121-CKLVFFAEDW diluted in cathepsin E assaybuffer (final concentration: 300 nM), the plates were strongly shakenfor 2 minutes. The enzymatic reaction was followed in a plate: visionreader (Perkin Elmer) (excitation wavelength: 630 nm; emission: 695 nm)for at least 30 minutes in a kinetic measurement detecting an increaseof MR121 fluorescence during the reaction time. The slope in the linearrange of the kinetic was calculated and the IC₅₀ of the test compoundswere determined using a four parameter equation for curve fitting.

In Vitro Transport Experiments

Bidirectional Transcellular Transport Using LLC-PK1 and L-MDR1 LLC-PK1Cells Exogenously Expressing the Human MDR1)

The method used for transport experiments was reported Schwab D, SchragP, Portmann R, Rühmann S. Operation procedure: LLC-PK1 cell lines,parental and transfected with human (MDR1) or mouse (mdr1a)Pglycoprotein to study transcellular transport by β-glycoprotein. ReportNo. 1008708. Jul. 1, 2002, and Schwab D, Schrag P, Portmann R.Validation report on in vitro β-glycoprotein transport of 16 referencecompounds in LLC-PK1 cells (parental) and MDR1 or mdr1a (Mouse multidrugresistance protein 1a) transfected LLC-PK1 cells and correlation to invivo brain penetration in mice.). The experiments were performed on aTECAN automated liquid handling system. Briefly, medium was removed fromall compartments and the medium of receiver side was replaced withculture medium. The trans-cellular transport measurements were initiatedby adding the substrate together with extracellular marker luciferyellow to the donor side. Inhibitors were added to both sides (1 μMelacridar). Transport experiments were performed both in thebasolateral-to-apical and apical-to-basolateral directions with 3 wellseach. The plates were incubated at 37° C. and 5% CO₂ in a Liconicincubator. Samples were taken from the donor and the opposite (acceptor)side after 2 hours incubation. Concentrations of substrate in bothcompartments were determined by scintillation counting (digoxin) or byLC-MS/MS. The extracellular marker (lucifer yellow) was quantified usinga spectrafluor plus reader at 430/535 nm (Ex/Em). In each experiment 3different inserts were used for each condition and a mean wascalculated.

Data Analysis

Bidirectional Transcellular Transport Using LLC-PK1 and L-MDR1 Cells

For the transcellular transport, the following equation was used fordata evaluation:

$P_{app} = {\frac{1}{A*C_{0}}*\frac{dQ}{dt}}$

Where P_(app), A, C_(O), and dQ/dt represent the apparent permeability,the filter surface area, the initial concentration, and the amounttransported per time period, respectively. P_(app) values werecalculated on the basis of a single time point (2 h).

Transport efflux ratios (ER) were calculated as follows:

$E\; R{= \frac{P_{app}BA}{P_{app}AB}}$

Where P_(app)BA is the permeability value in the basolateral-to-apicaldirection, and P_(app)AB the permeability value in theapical-to-basolateral direction. P_(app) were not corrected for flux ofthe extracellular marker lucifer yellow, which was used to assess thequality of the cell monolayers.

Results

TABLE 2 Pharmacological data, NF = in vitro no significant adductformation relative to control, A = less than 60% of control @ 30 mg/kgmouse, B = less than 90% of control @ 30 mg/kg mouse, C = IC₅₀ > 10 μMCYP GSH in vivo Cathepsin E Cathepsin D IC₅₀ [μM] Ex. human effect IC₅₀[μM] IC₅₀ [μM] 3A4 2D6 2C9 1 NF — 139 75 — C C 5 NF A 78 29 C — C 6 NF A79 38 C C C 7 NF B 182 37 C C C 24 — A 167 39 C C C 28 — — 7 16 C C C 41— — 56 45 C C C

Pharmaceutical Compositions

The compounds of formula I and the pharmaceutically acceptable salts canbe used as therapeutically active substances, e.g. in the form ofpharmaceutical preparations. The pharmaceutical preparations can beadministered orally, e.g. in the form of tablets, coated tablets,dragées, hard and soft gelatin capsules, solutions, emulsions orsuspensions. The administration can, however, also be effected rectally,e.g. in the form of suppositories, or parenterally, e.g. in the form ofinjection solutions.

The compounds of formula I and the pharmaceutically acceptable saltsthereof can be processed with pharmaceutically inert, inorganic ororganic carriers for the production of pharmaceutical preparations.Lactose, corn starch or derivatives thereof, talc, stearic acids or itssalts and the like can be used, for example, as such carriers fortablets, coated tablets, dragées and hard gelatin capsules. Suitablecarriers for soft gelatin capsules are, for example, vegetable oils,waxes, fats, semi-solid and liquid polyols and the like. Depending onthe nature of the active substance no carriers are however usuallyrequired in the case of soft gelatin capsules. Suitable carriers for theproduction of solutions and syrups are, for example, water, polyols,glycerol, vegetable oil and the like. Suitable carriers forsuppositories are, for example, natural or hardened oils, waxes, fats,semi-liquid or liquid polyols and the like.

The pharmaceutical preparations can, moreover, contain pharmaceuticallyacceptable auxiliary substances such as preservatives, solubilizers,stabilizers, wetting agents, emulsifiers, sweeteners, colorants,flavorants, salts for varying the osmotic pressure, buffers, maskingagents or antioxidants. They can also contain still othertherapeutically valuable substances.

Medicaments containing a compound of formula I or a pharmaceuticallyacceptable salt thereof and a therapeutically inert carrier are alsoprovided by the present invention, as is a process for their production,which comprises bringing one or more compounds of formula I and/orpharmaceutically acceptable salts thereof and, if desired, one or moreother therapeutically valuable substances into a galenicaladministration form together with one or more therapeutically inertcarriers.

The dosage can vary within wide limits and will, of course, have to beadjusted to the individual requirements in each particular case. In thecase of oral administration the dosage for adults can vary from about0.01 mg to about 1000 mg per day of a compound of general formula I orof the corresponding amount of a pharmaceutically acceptable saltthereof. The daily dosage may be administered as single dose or individed doses and, in addition, the upper limit can also be exceededwhen this is found to be indicated.

The following examples illustrate the present invention without limitingit, but serve merely as representative thereof. The pharmaceuticalpreparations conveniently contain about 1-500 mg, particularly 1-100 mg,of a compound of formula I. Examples of compositions according to theinvention are:

Example A Tablets of the Following Composition are Manufactured in theUsual Manner:

TABLE 3 possible tablet composition mg/tablet ingredient 5 25 100 500Compound of formula I 5 25 100 500 Lactose Anhydrous DTG 125 105 30 150Sta-Rx 1500 6 6 6 60 Microcrystalline Cellulose 30 30 30 450 MagnesiumStearate 1 1 1 1 Total 167 167 167 831

Manufacturing Procedure

1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.2. Dry the granules at 50° C.3. Pass the granules through suitable milling equipment.4. Add ingredient 5 and mix for three minutes; compress on a suitablepress.

Example B-1 Capsules of the Following Composition are Manufactured:

TABLE 4 possible capsule ingredient composition mg/capsule ingredient 525 100 500 Compound of formula I 5 25 100 500 Hydrous Lactose 159 123148 — Corn Starch 25 35 40 70 Talk 10 15 10 25 Magnesium Stearate 1 2 25 Total 200 200 300 600ingredient mg/capsule

Manufacturing Procedure

1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.2. Add ingredients 4 and 5 and mix for 3 minutes.3. Fill into a suitable capsule.

The compound of formula I, lactose and corn starch are firstly mixed ina mixer and then in a comminuting machine. The mixture is returned tothe mixer; the talc is added thereto and mixed thoroughly. The mixtureis filled by machine into suitable capsules, e.g. hard gelatin capsules.

Example B-2 Soft Gelatin Capsules of the Following Composition areManufactured:

TABLE 5 possible soft gelatin capsule ingredient composition ingredientmg/capsule Compound of formula I 5 Yellow wax 8 Hydrogenated Soya beanoil 8 Partially hydrogenated plant oils 34 Soya bean oil 110 Total 165

TABLE 6 possible soft gelatin capsule composition ingredient mg/capsuleGelatin 75 Glycerol 85% 32 Karion 83 8 (dry matter) Titan dioxide 0.4Iron oxide yellow 1.1 Total 116.5

Manufacturing Procedure

The compound of formula I is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example C Suppositories of the Following Composition are Manufactured:

TABLE 7 possible suppository composition ingredient mg/supp. Compound offormula I 15 Suppository mass 1285 Total 1300

Manufacturing Procedure

The suppository mass is melted in a glass or steel vessel, mixedthoroughly and cooled to 45° C. Thereupon, the finely powdered compoundof formula I is added thereto and stirred until it has dispersedcompletely. The mixture is poured into suppository moulds of suitablesize, left to cool; the suppositories are then removed from the mouldsand packed individually in wax paper or metal foil.

Example D Injection Solutions of the Following Composition areManufactured:

TABLE 8 possible injection solution composition ingredient mg/injectionsolution. Compound of formula I 3 Polyethylene Glycol 400 150 aceticacid q.s. ad pH 5.0 water for injection solutions ad 1.0 ml

Manufacturing Procedure

The compound of formula I is dissolved in a mixture of PolyethyleneGlycol 400 and water for injection (part). The pH is adjusted to 5.0 byacetic acid. The volume is adjusted to 1.0 ml by addition of theresidual amount of water. The solution is filtered, filled into vialsusing an appropriate overage and sterilized.

Example E Sachets of the Following Composition are Manufactured:

TABLE 9 possible sachet composition ingredient mg/sachet Compound offormula I 50 Lactose, fine powder 1015 Microcrystalline cellulose(AVICEL PH 102) 1400 Sodium carboxymethyl cellulose 14Polyvinylpyrrolidon K 30 10 Magnesium stearate 10 Flavoring additives 1Total 2500

Manufacturing Procedure

The compound of formula I is mixed with lactose, microcrystallinecellulose and sodium carboxymethyl cellulose and granulated with amixture of polyvinylpyrrolidone in water. The granulate is mixed withmagnesium stearate and the flavoring additives and filled into sachets.

Experimental Part

The following examples are provided for illustration of the invention.They should not be considered as limiting the scope of the invention,but merely as being representative thereof.

Experimental Part: Synthesis of Intermediates Intermediates I1A and I1B2-((S,2S)-2-Amino-3-fluoro-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrile(I1A) and2-((R,2S)-2-amino-3-fluoro-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrile(I1B)

Step 1:(R)—N-(2-fluoro-1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide(CAS #1404337-92-3, 2.8 g) and2-(N,S-dimethylsulfonimidoyl)-2-methylpropanenitrile (CAS #1629090-52-3,2.6 g) were dissolved in tetrahydrofuran (65 ml) and cooled to −75° C.Lithium bis(trimethylsilyl)amide (1.0 M in THF/ethylbenzene, 16.2 ml)was added dropwise and the mixture was stirred for 4 h at −75° C. Afteraddition of aqueous half-concentrated ammonium chloride solution thecooling bath was removed and stirring was continued for 10 min. Themixture was extracted with EtOAc, dried over sodium sulphate, filteredand concentrated to dryness. The crude material was purified by flashchromatography (silica gel, 0% to 100% EtOAc in n-heptane) to give(R)—N-((2S)-1-(2-cyano-N-methylpropan-2-ylsulfonimidoyl)-3-fluoro-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(1.05 μg, mixture of epimers) as yellow viscous oil. MS: m/z=420.2[M+H]⁺.

Step 2:(R)—N-((2S)-1-(2-cyano-N-methylpropan-2-ylsulfonimidoyl)-3-fluoro-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(1.0 g, mixture of epimers) was dissolved in MeOH (9.8 ml) and cooled to0-5° C. After addition of HCl (4M in dioxane, 1.79 ml) the mixture wasstirred for 3 h at 0-5° C. and stored overnight at 4° C. The reactionmixture was poured into aqueous saturated sodium bicarbonate solutionand extracted 3 times with dichloromethane. The organic layers weredried over sodium sulphate, filtered and concentrated. The crudematerial was purified by flash chromatography (silica gel, 0% to 100%EtOAc in n-heptane) to give the first-eluting isomer2-((S,2S)-2-amino-3-fluoro-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrile(211 mg) as light yellow viscous oil, MS: m/z=316.1 [M+H]⁺ and thesecond-eluting isomer2-((R,2S)-2-amino-3-fluoro-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrile(296 mg) as light yellow viscous oil, MS: m/z=316.1 [M+H]⁺.

Intermediate I2A(1S,3S)-5-amino-3-(fluoromethyl)-3-(2-fluorophenyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide

2-((2S)-2-amino-3-fluoro-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrile(Intermediate I1A, 200 mg) and copper (I) chloride (65.3 mg) werecombined under argon with ethanol (6.04 ml) to give a yellow suspension.The reaction mixture was stirred for 1.5 h at 75° C. The reactionmixture was cooled to room temperature and poured into 25% aqueousammonia solution (3 ml) and water (12 ml) and extracted withdichloromethane. The organic layers were dried over MgSO₄ andconcentrated in vacuo. The residue was diluted with EtOAc, filtered overa 20 g silica-NH₂-column, evaporated and dried to give(1S,3S)-5-amino-3-(fluoromethyl)-3-(2-fluorophenyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide (173 mg) as light yellow solid. MS: m/z=316.1 [M+H]⁺.

Intermediate I3A tert-butyl((1S,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: A solution of(1S,3S)-5-amino-3-(fluoromethyl)-3-(2-fluorophenyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide (Intermediate I2A, 165 mg) in dichloromethane (7.27 ml) wascooled under argon in an ice bath. Trifluoromethanesulfonic acid (1.57g) was added and the solution was allowed to warm to room temperature.N-iodosuccinimide (141 mg) was added and the mixture was stirred for 3.5h at room temperature. More N-iodosuccinimide (23.5 mg) was added andstirring was continued for 2 h. More N-iodosuccinimide (23.5 mg) wasadded and stirred overnight. The dark purple mixture was added dropwiseto a sat. aqueous NaHCO₃ solution (25 ml). The aqueous layer wasseparated and extracted once more with dichloromethane. The organiclayers were washed with aqueous 0.1M sodiumthiosulphate solution, driedover MgSO4, filtered and concentrated in vacuo. The crude material waspurified by flash chromatography (NH₂-modified silica gel, 0% to 100%EtOAc in n-heptane) to give(1S,3S)-5-amino-3-(2-fluoro-5-iodophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide (150 mg) as off-white solid. MS: m/z=442.1 [M+H]⁺.

Step 2:(1S,3S)-5-Amino-3-(2-fluoro-5-iodophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide (145 mg) was dissolved in dichloromethane (4.1 ml) under argon.After addition of BOC-Anhydride (75.3 mg) the mixture was stirred for 1day. The reaction mixture was evaporated and the crude material waspurified by flash chromatography (silica gel, 0% to 50% EtOAc inn-heptane) to give tert-butyl((1S,5S)-5-(2-fluoro-5-iodophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(169 mg) as off-white solid. MS: m/z=542.2 [M+H]+.

Step 3: tert-Butyl((1S,5S)-5-(2-fluoro-5-iodophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(162 mg), ethynyltrimethylsilane (58.8 mg),bis(triphenylphosphine)palladium (II) chloride (14.7 mg), copper (I)iodide (2.28 mg) and triethylamine (90.8 mg) were mixed under argon withTHF (2.66 ml) and stirred for 1 h at room temperature. The mixture wasdiluted with EtOAc and filtered through a glass fiber filter. Thefiltrate was evaporated and the crude material was purified by flashchromatography (silica gel, 0% to 100% EtOAc in n-heptane) to givetert-butyl((1S,5S)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(147 mg) as off-white solid. MS: m/z=512.2 [M+H]⁺.

Step 4: To remove traces of Cu and Pd, the starting material was treatedwith a scavenger: tert-butyl((1S,5S)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-5-(fluoroethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(142 mg) was dissolved in dichloromethane (4 ml) under argon. Afteraddition of 3-mercaptopropyl ethyl sulfide silica (96.4 mg) the mixturewas stirred under argon overnight. The scavenger was filtered off andwashed well with ethyl acetate. The almost colorless solution wasevaporated, re-dissolved in dichloromethane (4.04 ml) and cooled to 0°C. After addition of tetrabutylammonium fluoride (1M in THF, 305 μl) themixture was stirred for 45 min at 0° C. The mixture was diluted withdichloromethane and washed with water. The org. layer was dried oversodium sulphate, filtered and evaporated to give tert-butyl((1S,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(122 mg) as off-white solid. MS: m/z=440.2 [M+H]⁺. The product was usedin the next step without further purification.

Intermediate I2B(1R,3S)-5-amino-3-(fluoromethyl)-3-(2-fluorophenyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide

In analogy to the synthesis of Intermediate I2A,2-((R,2S)-2-amino-3-fluoro-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrile(Intermediate I1B) was converted to(1R,3S)-5-amino-3-(fluoromethyl)-3-(2-fluorophenyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with CuCl in ethanol at 75° C. for 5 h. Lightyellow solid. MS: m/z=316.1 [M+H]⁺

Intermediate I3B tert-butyl((1R,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 1,(1R,3S)-5-amino-3-(fluoromethyl)-3-(2-fluorophenyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide (Intermediate I2B) was converted to(1R,3S)-5-amino-3-(2-fluoro-5-iodophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with N-iodosuccinimide in dichloromethane in thepresence of trifluoromethanesulfonic acid.

Light yellow solid. MS: m/z=442.1 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I3A, step 2,(1R,3S)-5-amino-3-(2-fluoro-5-iodophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide was converted to tert-butyl((1R,5S)-5-(2-fluoro-5-iodophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with BOC-Anhydride in dichloromethane. Off-white solid. MS:m/z=542.0 [M+H]⁺.

Step 3: In analogy to the synthesis of Intermediate I3A, step 3,tert-butyl((1R,5S)-5-(2-fluoro-5-iodophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1R,5S)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Off-white solid. MS: m/z=512.2 [M+H]⁺.

Step 4: In analogy to the synthesis of Intermediate I3A, step 4,tert-butyl((1R,5S)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1R,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with tetrabutylammonium fluoride in dichloromethane.Off-white solid. MS: m/z=440.2 [M+H]^(|).

Intermediates I4A and I4B(R)—N—((R)-1-((R)-2-cyano-N-methylpropan-2-ylsulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(I4A) and(R)—N—((R)-1-((S)-2-cyano-N-methylpropan-2-ylsulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(I4B)

2-(N,S-dimethylsulfonimidoyl)-2-methylpropanenitrile (CAS #1629090-52-3,2.93 g) was dissolved in dichloromethane (60 ml) and cooled to −75° C.under argon. Lithium bis(trimethylsilyl)amide, 1.0 M in THF/ethylbenzene(18.3 ml) was added dropwise and the mixture was stirred for 1 h at −70°C. A solution of(R)—N-(1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (CAS#1606166-80-6, 3.4 g) in dichloromethane (17.5 ml) was added dropwisewithin 5 min at −75° C. Stirring was continued at −75° C. for 80 min.Lithium bis(trimethylsilyl)amide, 1.0 M in THF/ethylbenzene (10.5 ml)was added dropwise and the mixture was stirred for 70 min at −70° C. Thereaction was quenched by addition of aqueous half concentrated ammoniumchloride solution. The temperature was allowed to rise to +5° C. Thelayers were separated and the org. layer was washed 3 times with water,dried over sodium sulphate and concentrated. The crude material waspurified by flash chromatography (silica gel, 0% to 100% EtOAc inn-heptane) to give the first-eluting isomer(R)—N—((R)-1-((R)-2-cyano-N-methylpropan-2-ylsulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I4A, 1.135 g, contains approximately 5% Intermediate I4B)as light yellow waxy solid, MS: m/z=402.2 [M+H]⁺ and the second-elutingisomer(R)—N—((R)-1-((S)-2-cyano-N-methylpropan-2-ylsulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I4B, 0.692 g, contains approximately 10% Intermediate I4A)as light yellow oil, MS: m/z=402.2 [M+H]⁺.

Intermediate I5A(1R,3R)-5-amino-3-(2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide

Step 1: In analogy to the synthesis of Intermediates I1A and I1B, step2,(R)—N—((R)-1-((R)-2-cyano-N-methylpropan-2-ylsulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I4A) was converted to2-((R,2R)-2-amino-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrileby treatment with HCl in methanol and dioxane at 0-5° C. Colorless oil.MS: m/z=298.1 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I2A,2-((R,2R)-2-amino-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrilewas converted to(1R,3R)-5-amino-3-(2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with CuCl in ethanol at 75° C. for 2 h. Off-whitesolid. MS: m/z=298.1 [M+H]⁺.

Intermediate I6A tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 1,(1R,3R)-5-amino-3-(2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide (Intermediate I5A) was converted to(1R,3R)-5-amino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with N-iodosuccinimide in dichloromethane in thepresence of trifluoromethanesulfonic acid. Light yellow solid. MS:m/z=424.0 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I3A, step 2,(1R,3R)-5-amino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide was converted to tert-butyl((1R,5R)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with BOC-Anhydride in dichloromethane. Off-white solid. MS:m/z=522.2 [M−H]⁻.

Step 3: In analogy to the synthesis of Intermediate I3A, step 3,tert-butyl((1R,5R)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1R,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Light brown solid. MS: m/z=394.2 [M+H-BOC]⁺.

Step 4: In analogy to the synthesis of Intermediate I3A, step 4,tert-butyl((1R,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with tetrabutylammonium fluoride in dichloromethane.Colorless foam. MS: m/z=420.2 [M−H]⁻.

Intermediate I5B(1S,3R)-5-amino-3-(2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide

Step 1: In analogy to the synthesis of Intermediates I1A and I1B, step2,(R)—N—((R)-1-((S)-2-cyano-N-methylpropan-2-ylsulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I4B) was converted to2-((S,2R)-2-amino-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrileby treatment with HCl in methanol and dioxane at 0-5° C. Colorless oil.MS: m/z=298.1 [M+H]f.

Step 2: In analogy to the synthesis of Intermediate I2A,2-((S,2R)-2-amino-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrilewas converted to(1S,3R)-5-amino-3-(2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with CuCl in ethanol at 75° C. for 2 h. Off-whitefoam. MS: m/z=298.1 [M+H]⁺.

Intermediate I6B tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 1,(1S,3R)-5-amino-3-(2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide (Intermediate I5B) was converted to(1S,3R)-5-amino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with N-iodosuccinimide in dichloromethane in thepresence of trifluoromethanesulfonic acid. Off-white solid. MS:m/z=424.1 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I3A, step 2,(1S,3R)-5-amino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide was converted to tert-butyl((1S,5R)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with BOC-Anhydride in dichloromethane. Colorless solid. MS:m/z=522.2 [M−H]⁺.

Step 3: In analogy to the synthesis of Intermediate I3A, step 3,tert-butyl((1S,5R)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1S,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Light yellow solid. MS: m/z=494.2 [M+H]⁺.

Step 4: In analogy to the synthesis of Intermediate I3A, step 4,tert-butyl((1S,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with tetrabutylammonium fluoride in dichloromethane.Colorless foam. MS: m/z=322.1 [M+H-BOC]^(|).

Intermediate I7AN-[(1R)-2-[S-(1-cyano-1-methyl-ethyl)-N-(trideuteriomethyl)sulfonimidoyl]-1-(2-fluorophenyl)-1-methyl-ethyl]-2-methyl-propane-2-sulfinamide

Step 1: 2-Methyl-2-(S-methylsulfonimidoyl)propanenitrile (6.68 g) wasdissolved in dimethoxyethane (109 ml) and cooled to 0-5° C. Afteraddition of sodium hydride (60% dispersion in mineral oil, 1.89 g) themixture was stirred for 15 min at 0-5° C., the cooling bath was removedand the mixture was stirred for 1 h at room temperature. The mixture wascooled again to 0-5° C. After addition of iodomethane-D3 (6.56 g)stirring was continued for 1 h at room temperature followed by 18 h at50° C. The mixture was allowed to cool to room temperature. Afteraddition of aqueous saturated sodium bicarbonate solution the mixturewas extracted with ethyl acetate. The organic layers were washed withbrine, combined, dried over sodium sulphate and concentrated. The crudematerial was purified by flash chromatography (silica gel, 0% to 100%EtOAc in n-heptane) to give2-methyl-2-[S-methyl-N-(trideuteriomethyl)sulfonimidoyl]propanenitrileas light brown oil. MS: m/z=164.1 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I4A,2-methyl-2-[S-methyl-N-(trideuteriomethyl)sulfonimidoyl]propanenitrilewas reacted first with lithium bis(trimethylsilyl)amide followed bytreatment with(R)—N-(1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide togive after chromatography (silica gel, 0% to 100% EtOAc in n-heptane)the first-eluting isomerN-[(1R)-2-[S-(1-cyano-1-methyl-ethyl)-N-(trideuteriomethyl)sulfonimidoyl]-1-(2-fluorophenyl)-1-methyl-ethyl]-2-methyl-propane-2-sulfinamide(Intermediate I7A, contains approximately 5% of the second-elutingisomer) as light yellow solid, MS: m/z=405.2 [M+H]⁺

Intermediate I8A(1R,3R)-3-(2-fluorophenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine

Step 1: In analogy to the synthesis of Intermediates I1A and I1B, step2,N-[(1R)-2-[S-(1-cyano-1-methyl-ethyl)-N-(trideuteriomethyl)sulfonimidoyl]-1-(2-fluorophenyl)-1-methyl-ethyl]-2-methyl-propane-2-sulfinamide(Intermediate I7A) was converted to2-[S-[(2R)-2-amino-2-(2-fluorophenyl)propyl]-N-(trideuteriomethyl)sulfonimidoyl]-2-methyl-propanenitrileby treatment with HCl in methanol and dioxane at 0-5° C. Colorless oil.MS: m/z=301.1 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I2A,2-[S-[(2R)-2-amino-2-(2-fluorophenyl)propyl]-N-(trideuteriomethyl)sulfonimidoyl]-2-methyl-propanenitrilewas converted to(1R,3R)-3-(2-fluorophenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amineby treatment with CuCl in ethanol at 75° C. Off-white solid. MS:m/z=301.1 [M+H]⁺.

Intermediate I9A tert-ButylN-[(1R,3R)-3-(5-ethynyl-2-fluoro-phenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 1,(1R,3R)-3-(2-fluorophenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine(Intermediate I8A) was converted to(1R,3R)-3-(2-fluoro-5-iodo-phenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amineby treatment with N-iodosuccinimide in dichloromethane in the presenceof trifluoromethanesulfonic acid. Off-white solid. MS: m/z=427.1 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I3A, step 2,(1R,3R)-3-(2-fluoro-5-iodo-phenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-aminewas converted to tert-butylN-[(1R,3R)-3-(2-fluoro-5-iodo-phenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamateby treatment with BOC-Anhydride in dichloromethane. Colorless solid. MS:m/z=527.2 [M+H]⁺.

Step 3: In analogy to the synthesis of Intermediate I3A, step 3,tert-butylN-[(1R,3R)-3-(2-fluoro-5-iodo-phenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamatewas converted to tert-butylN-[(1R,3R)-3-[2-fluoro-5-(2-trimethylsilylethynyl)phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Light brown solid. MS: m/z=497.3 [M+H]⁺.

Step 4: In analogy to the synthesis of Intermediate I3A, step 4,tert-butylN-[(1R,3R)-3-[2-fluoro-5-(2-trimethylsilylethynyl)phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamatewas converted to tert-butylN-[(1R,3R)-3-(5-ethynyl-2-fluoro-phenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamateby treatment with tetrabutylammonium fluoride in dichloromethane.Colorless solid. MS: m/z=425.3 [M+H]⁺.

Intermediates I10A and I10B(R)—N—((R)-1-((R)-1-cyano-N-methylcyclopentanesulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(I10A) and(R)—N—((R)-1-((S)-1-cyano-N-methylcyclopentanesulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(I10B)

Step 1: To a stirred solution of 1-(methylthio)cyclopentanecarbonitrile(7.91 g) in dichloromethane (128 ml) 3-chlorobenzoperoxoic acid (10.9 g)was added in one portion at 0° C. The white suspension was stirred at 0°C. for 30 min. The mixture was filtered. A 1M solution of potassiumcarbonate (1/3) was mixed with a half sat. solution of sodiumthiosulfate (2/3). The organic layer was extracted immediately with 1×20ml of this solution. The aqueous layer was back-extracted with 1×30 mldichloromethane. The combined organic layers were dried over Na₂SO₄ andconcentrated. The crude 1-(methylsulfinyl)cyclopentanecarbonitrile wasused for the next step without further purification.

Step 2: 1-(Methylsulfinyl)cyclopentanecarbonitrile (6.749 g),4-nitrobenzenesulfonamide (9.37 g), silver nitrate (525 mg) and4,4′,4″-tri-tert-butyl-2,2′:6′,2″-terpyridine (1.24 g) were combined inMeCN (129 ml). After 20 min, (diacetoxyiodo)benzene (18.7 g) was addedand stirred for 24 h at 60° C. The solution was filtered, and theprecipitate was washed with dichloromethane. The filtrate wasconcentrated and the crude material was purified by flash chromatography(silica gel, 80 g, 100% DCM) to giveN-[(1-cyanocyclopentyl)-methyl-oxo-?⁶⁻sulfanylidene]-4-nitro-benzenesulfonamide(12.816 g).

Step 3: To a solution ofN-[(1-cyanocyclopentyl)-methyl-oxo-6-sulfanylidene]-4-nitro-benzenesulfonamide(13.192 g) in acetonitrile (246 ml) was added at 23° C. cesium carbonate(21.6 g) followed by the addition of thiophenol (6.51 g) and thereaction mixture was stirred at 23° C. for 6 h. Poured into brine (100ml), extracted twice with ethyl acetate(50 ml), dried the organic layersover Na2SO4, filtered, and concentrated to dryness. The crude materialwas purified by flash chromatography (silica gel, 80 g, 20% to 100%EtOAc in heptane) to give1-(S-methylsulfonimidoyl)cyclopentanecarbonitrile (5.433 g) as a slightyellow oil. MS: m/z=172.9 [M+H]⁺.

Step 4: In analogy to the synthesis of Intermediate I7A, step 1,1-(S-methylsulfonimidoyl)cyclopentanecarbonitrile was alkylated withmethyl iodide in the presence of sodium hydride to give1-(N,S-dimethylsulfonimidoyl)cyclopentane-1-carbonitrile as light yellowoil. MS: m/z=186.1 [M]⁺.

Step 5: In analogy to the synthesis of Intermediate I4A,1-(N,S-dimethylsulfonimidoyl)cyclopentane-1-carbonitrile was reactedfirst with lithium bis(trimethylsilyl)amide followed by treatment with(R)—N-(1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide togive after chromatography (silica gel, 0% to 100% EtOAc in n-heptane)the first-eluting isomer(R)—N—((R)-1-((R)-1-cyano-N-methylcyclopentanesulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I10A) as light brown solid, MS: m/z=428.2 [M+H]⁺; and thesecond-eluting isomer(R)—N—((R)-1-((S)-1-cyano-N-methylcyclopentanesulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I10B) as light yellow solid, MS: m/z=428.3 [M+H]⁺.

Intermediate I11A(6R,8R)-10-amino-8-(2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide

Step 1: In analogy to the synthesis of Intermediates I1A and I1B, step2,(R)—N—((R)-1-((R)-1-cyano-N-methylcyclopentanesulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I10A) was converted to1-((R,2R)-2-amino-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)cyclopentanecarbonitrileby treatment with HCl in methanol and dioxane at 0-5° C. Colorless oil.MS: m/z=324.2 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I2A,1-((R,2R)-2-amino-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)cyclopentanecarbonitrilewas converted to(6R,8R)-10-amino-8-(2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide by treatment with CuCl in ethanol at 75° C. Light brown gum. MS:m/z=324.2 [M+H]⁺.

Intermediate I12A tert-butyl((6R,8R)-8-(5-ethynyl-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 1,(6R,8R)-10-amino-8-(2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide (Intermediate I11A) was converted to(6R,8R)-10-amino-8-(2-fluoro-5-iodophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide by treatment with N-iodosuccinimide in dichloromethane in thepresence of trifluoromethanesulfonic acid. Brown foam. MS: m/z=450.1[M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I3A, step 2,(6R,8R)-10-amino-8-(2-fluoro-5-iodophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide was converted to tert-butyl((6R,8R)-8-(2-fluoro-5-iodophenyl)-8-methyl-6-(methylamino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with BOC-Anhydride in dichloromethane. Off-white solid. MS:m/z=550.3 [M+H]⁺.

Step 3: In analogy to the synthesis of Intermediate I3A, step 3,tert-butyl((6R,8R)-8-(2-fluoro-5-iodophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamatewas converted to tert-butyl((6R,8R)-8-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Colorless solid. MS: m/z=520.4 [M+H]⁺.

Step 4: In analogy to the synthesis of Intermediate I3A, step 4,tert-butyl((6R,8R)-8-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamatewas converted to tert-butyl((6R,8R)-8-(5-ethynyl-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with tetrabutylammonium fluoride in dichloromethane.Colorless solid. MS: m/z=448.3 [M+H]⁺.

Intermediate I11B(6S,8R)-10-amino-8-(2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide

Step 1: In analogy to the synthesis of Intermediates I1A and I1B, step2,(R)—N—((R)-1-((S)-1-cyano-N-methylcyclopentanesulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I10B) was converted to1-((S,2R)-2-amino-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)cyclopentanecarbonitrileby treatment with HCl in methanol and dioxane at 0-5° C. Colorless oil.MS: m/z=324.2 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I2A,1-((S,2R)-2-amino-2-(2-fluorophenyl)-N-methylpropylsulfonimidoyl)cyclopentanecarbonitrilewas converted to(6S,8R)-10-amino-8-(2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide by treatment with CuCl in ethanol at 75° C. Light brown gum. MS:m/z=324.2 [M+H]⁺.

Intermediate I12B tert-butyl((6S,8R)-8-(5-ethynyl-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 1,(6S,8R)-10-amino-8-(2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide (Intermediate I11B) was converted to(6S,8R)-10-amino-8-(2-fluoro-5-iodophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide by treatment with N-iodosuccinimide in dichloromethane in thepresence of trifluoromethanesulfonic acid. Brown gum. MS: m/z=450.1[M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I3A, step 2,(6S,8R)-10-amino-8-(2-fluoro-5-iodophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide was converted to tert-butyl((6S,8R)-8-(2-fluoro-5-iodophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with BOC-Anhydride in dichloromethane. Colorless solid. MS:m/z=550.2 [M+H]⁺.

Step 3: In analogy to the synthesis of Intermediate I3A, step 3,tert-butyl((6S,8R)-8-(2-fluoro-5-iodophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamatewas converted to tert-butyl((6S,8R)-8-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Off-white solid. MS: m/z=520.4 [M+H]⁺.

Step 4: In analogy to the synthesis of Intermediate I3A, step 4,tert-butyl((6S,8R)-8-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamatewas converted to tert-butyl((6S,8R)-8-(5-ethynyl-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with tetrabutylammonium fluoride in dichloromethane.Colorless solid. MS: m/z=448.3 [M+H]⁺.

Intermediates I14A and I14B tert-butylN-[(1R,3R)-1-cyclopropylimino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-yl]carbamate(I14A) and tert-butylN-[(1S,3R)-1-cyclopropylimino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-yl]carbamate(I14B)

Step 1: 1-(2-Fluoro-5-iodophenyl)ethanone (5 μg) and(R)-(+)-2-methyl-2-propanesulfinamide (4.59 g) were dissolved in THF(38.6 ml). After addition of titanium(iv) ethoxide (8.64 g) the mixturewas stirred at room temperature overnight then heated up to 70° C. andstirred for 5 h. After cooling to room temperature, water (3 ml), ethylacetate (50) and Dicalite were added and the mixture was stirred for 10min and filtered. The filtrate was concentrated and the residual liquidoil was purified by chromatography (silica gel, 0% to 60% EtOAc inn-heptane) to give(R)—N-(1-(2-fluoro-5-iodophenyl)ethylidene)-2-methylpropane-2-sulfinamideas light yellow solid. MS: m/z=368.1 [M+H]⁺.

Step 2: To a stirred solution of2-methyl-2-(S-methylsulfonimidoyl)propanenitrile (5 g) in1,2-dichloroethane (33.3 ml) were added cyclopropylboronic acid (6.76g), copper (II) acetate (6.21 g), 2,2′-bipyridine (4.27 g) and sodiumcarbonate (10.9 g). The reaction mixture was stirred under airatmosphere for 5 min, then heated up to 90° C. and stirred for 3 h. Thereaction mixture was cooled down to room temperature and stirredovernight, filtered through 50 g silica gel-column. The filtrate wasconcentrated to get the crude product. The product was purified usingflash chromatography (silica gel, 0% to 100% EtOAc in n-heptane) to give2-(N-cyclopropyl-S-methylsulfonimidoyl)-2-methylpropanenitrile as lightyellow liquid. MS: m/z=187.1 [M+H]^(|).

Step 3: In analogy to the synthesis of Intermediate I4A,2-(N-cyclopropyl-S-methylsulfonimidoyl)-2-methylpropanenitrile wasreacted first with lithium bis(trimethylsilyl)amide followed bytreatment with(R)—N-(1-(2-fluoro-5-iodophenyl)ethylidene)-2-methylpropane-2-sulfinamideto give(R)—N-((2R)-1-(2-cyano-N-cyclopropylpropan-2-ylsulfonimidoyl)-2-(2-fluoro-5-iodophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(mixture of 2 isomers as light yellow oil, MS: m/z=554.3 [M+H]⁺.

Step 4: In analogy to the synthesis of Intermediates I1A and I1B, step2,(R)—N-((2R)-1-(2-cyano-N-cyclopropylpropan-2-ylsulfonimidoyl)-2-(2-fluoro-5-iodophenyl)propan-2-yl)-2-methylpropane-2-sulfinamidewas converted to2-((2R)-2-amino-N-cyclopropyl-2-(2-fluoro-5-iodophenyl)propylsulfonimidoyl)-2-methylpropanenitrile(mixture of 2 isomers) by treatment with HCl in methanol and dioxane at0-5° C. Light yellow oil. MS: m/z=450.3 [M+H]⁺.

Step 5: In analogy to the synthesis of Intermediate I2A,2-((2R)-2-amino-N-cyclopropyl-2-(2-fluoro-5-iodophenyl)propylsulfonimidoyl)-2-methylpropanenitrilewas converted to(3R)-5-amino-1-(cyclopropylimino)-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide (mixture of 2 isomers, not pure) by treatment with CuCl inethanol. Light green oil. MS: m/z=450.3 [M+H]⁺.

Step 6: In analogy to the synthesis of Intermediate I3A, step 2,(3R)-5-amino-1-(cyclopropylimino)-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide was treated with BOC-anhydride in dichloromethane to give afterchromatography (silica gel, 0% to 80% EtOAc in n-heptane) thefirst-eluting isomer tert-butylN-[(1R,3R)-1-cyclopropylimino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-yl]carbamate(Intermediate I14A, off-white solid, MS: m/z=550.4 [M+H]⁺) and thesecond-eluting isomer tert-butylN-[(1S,3R)-1-cyclopropylimino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-yl]carbamate(Intermediate I14B, off-white solid, MS: m/z=550.4 [M+H]⁺)

Intermediate I15A tert-butyl((1R,5R)-1-(cyclopropylimino)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 3,tert-butyl((1R,5R)-1-(cyclopropylimino)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I14A) was converted to tert-butyl((1R,5R)-1-(cyclopropylimino)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Yellow solid. MS: m/z=520.5 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I3A, step 4,tert-butyl((1R,5R)-1-(cyclopropylimino)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1R,5R)-1-(cyclopropylimino)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with tetrabutylammonium fluoride in dichloromethane.Off-white solid. MS: m/z=448.4 [M+H]⁺.

Intermediate I15B tert-butyl((1S,5R)-1-(cyclopropylimino)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 3,tert-butyl((1S,5R)-1-(cyclopropylimino)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I14B) was converted to tert-butyl((1S,5R)-1-(cyclopropylimino)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Off-white solid. MS: m/z=520.5 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I3A, step 4,tert-butyl((1S,5R)-1-(cyclopropylimino)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1S,5R)-1-(cyclopropylimino)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with tetrabutylammonium fluoride in dichloromethane.Colorless solid. MS: m/z=448.4 [M+H]⁺.

Intermediates I16A and I16B(R)—N—((R)-1-((S)-2-cyano-N-(2,2,2-trifluoroethyl)propan-2-ylsulfonimidoyl)-2-(2-fluoro-5-iodophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(I16A) and(R)—N—((R)-1-((R)-2-cyano-N-(2,2,2-trifluoroethyl)propan-2-ylsulfonimidoyl)-2-(2-fluoro-5-iodophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(I16B)

Step 1: 2-Methyl-2-(S-methylsulfonimidoyl)propanenitrile (250 mg) wasdissolved in trifluoroacetic acid (16.3 g) and cooled in an ice-bath.Sodium borohydride (388 mg) was added in one portion. The cooling bathwas removed and the mixture was stirred for 3.5 h at room temperature. Asecond batch of sodium borohydride (259 mg) was added and stirring wascontinued for 2 h. The mixture was concentrated and taken up in conc.sodiumhydrogen carbonate solution and dichloromethane. Additionalsodiumhydrogen carbonate was added until the pH was >7. After stirringfor 5 min, the layers were separated. The aqueous layer was extractedtwice more with dichloromethane. The organic layers were dried oversodium sulphate and concentrated. The product was purified using flashchromatography (silica gel, 0% to 100% dichloromethane in n-heptane) togive2-methyl-2-(S-methyl-N-(2,2,2-trifluoroethyl)sulfonimidoyl)propanenitrile(161 mg) as colorless solid. MS: m/z=229.1 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I4A2-methyl-2-(S-methyl-N-(2,2,2-trifluoroethyl)sulfonimidoyl)propanenitrilewas reacted first with lithium bis(trimethylsilyl)amide followed bytreatment with(R)—N-(1-(2-fluoro-5-iodophenyl)ethylidene)-2-methylpropane-2-sulfinamideto give after chromatography (silica gel, 0% to 100% EtOAc in n-heptane)the first-eluting isomer(R)—N—((R)-1-((S)-2-cyano-N-(2,2,2-trifluoroethyl)propan-2-ylsulfonimidoyl)-2-(2-fluoro-5-iodophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I16A, colorless oil, MS: m/z=596.2 [M+H]^(|)) and thesecond-eluting isomer(R)—N—((R)-1-((R)-2-cyano-N-(2,2,2-trifluoroethyl)propan-2-ylsulfonimidoyl)-2-(2-fluoro-5-iodophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I16B, colorless solid, MS: m/z=596.2 [M+H]⁺).

Intermediate I17A tert-butyl((1S,5R)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: In analogy to the synthesis of Intermediates I1A and I1B, step2,(R)—N—((R)-1-((S)-2-cyano-N-(2,2,2-trifluoroethyl)propan-2-ylsulfonimidoyl)-2-(2-fluoro-5-iodophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I16A) was converted to2-((S,2R)-2-amino-2-(2-fluoro-5-iodophenyl)-N-(2,2,2-trifluoroethyl)propylsulfonimidoyl)-2-methylpropanenitrileby treatment with HCl in methanol and dioxane at 0-5° C. Colorless gum.MS: m/z=492.1 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I2A,2-((S,2R)-2-amino-2-(2-fluoro-5-iodophenyl)-N-(2,2,2-trifluoroethyl)propylsulfonimidoyl)-2-methylpropanenitrilewas converted to(1S,3R)-5-amino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with CuCl in ethanol. Colorless solid. MS:m/z=492.1 [M+H]⁺.

Step 3: In analogy to the synthesis of Intermediate I3A, step 2,(1S,3R)-5-amino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide was treated with BOC-anhydride in dichloromethane to givetert-butyl((1S,5R)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateas colorless foam. MS: m/z=592.07 [M+H]⁺

Intermediate I18A tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 3,tert-butyl((1S,5R)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I17A) was converted to tert-butyl((1S,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Light brown solid. MS: m/z=560.3 [M−H]⁻.

Step 2: In analogy to the synthesis of Intermediate I3A, step 4,tert-butyl((1S,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with tetrabutylammonium fluoride in dichloromethane.Colorless solid. MS: m/z=488.3 [M−H]⁻.

Intermediate I17B tert-butyl((1R,5R)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: In analogy to the synthesis of Intermediates I1A and I1B, step2,(R)—N—((R)-1-((R)-2-cyano-N-(2,2,2-trifluoroethyl)propan-2-ylsulfonimidoyl)-2-(2-fluoro-5-iodophenyl)propan-2-yl)-2-methylpropane-2-sulfinamide(Intermediate I16B) was converted to2-((R,2R)-2-amino-2-(2-fluoro-5-iodophenyl)-N-(2,2,2-trifluoroethyl)propylsulfonimidoyl)-2-methylpropanenitrileby treatment with HCl in methanol and dioxane at 0-5° C. Colorless oil.MS: m/z=492.1 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I2A,2-((R,2R)-2-amino-2-(2-fluoro-5-iodophenyl)-N-(2,2,2-trifluoroethyl)propylsulfonimidoyl)-2-methylpropanenitrilewas converted to(1R,3R)-5-amino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with CuCl in ethanol. Colorless solid. MS:m/z=492.1 [M+H]⁺.

Step 3: In analogy to the synthesis of Intermediate I3A, step 2,(1R,3R)-5-amino-3-(2-fluoro-5-iodophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide was treated with BOC-anhydride in dichloromethane to givetert-butyl((1R,5R)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateas colorless foam. MS: m/z=590.3 [M−H]⁻

Intermediate I18B tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 3,tert-butyl((1R,5R)-5-(2-fluoro-5-iodophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I17B) was converted to tert-butyl((1R,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Light yellow solid. MS: m/z=560.3 [M−H]⁻.

Step 2: In analogy to the synthesis of Intermediate I3A, step 4,tert-butyl((1R,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with tetrabutylammonium fluoride in dichloromethane. Lightyellow solid. MS: m/z=488.4 [M−H]⁻.

Intermediates I19A and I19B tert-butyl((1R,5R)-5-(2-fluoro-5-iodophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(I19A) and tert-butyl((1S,5R)-5-(2-fluoro-5-iodophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(I19B)

Step 1: In analogy to the synthesis of Intermediate I4A2-(N-cyclopropyl-S-methylsulfonimidoyl)-2-methylpropanenitrile wasreacted first with lithium bis(trimethylsilyl)amide followed bytreatment with(R,E)-N-(1-(2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide togive(R)—N-((2R)-1-(2-cyano-N-cyclopropylpropan-2-ylsulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamideas a mixture of two isomers. Light yellow oil, MS: m/z=428.4 [M+H]⁺)

Step 2: In analogy to the synthesis of Intermediates I1A and I1B, step2,(R)—N-((2R)-1-(2-cyano-N-cyclopropylpropan-2-ylsulfonimidoyl)-2-(2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamidewas converted to2-((2R)-2-amino-N-cyclopropyl-2-(2-fluorophenyl)propylsulfonimidoyl)-2-methylpropanenitrile(mixture of two isomers) by treatment with HCl in methanol and dioxaneat 0-5° C. Off-white oil. MS: m/z=324.3 [M+H]⁺.

Step 3: In analogy to the synthesis of Intermediate I2A,2-((2R)-2-amino-N-cyclopropyl-2-(2-fluorophenyl)propylsulfonimidoyl)-2-methylpropanenitrilewas converted to(3R)-5-amino-1-(cyclopropylimino)-3-(2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide (mixture of two isomers) by treatment with CuCl in ethanol at75° C. Light green solid. MS: m/z=324.2 [M+H]⁺.

Step 4: In analogy to the synthesis of Intermediate I3A, step 1,(3R)-5-amino-1-(cyclopropylimino)-3-(2-fluorophenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide was treated with N-iodosuccinimide in dichloromethane in thepresence of trifluoromethanesulfonic acid to give as an unexpectedproduct(3R)-5-amino-3-(2-fluoro-5-iodophenyl)-1-imino-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide (mixture of two isomers, could not be obtained pure and was usedas a crude product for the next step.)

Step 5: In analogy to the synthesis of Intermediate I3A, step 2, thecrude(3R)-5-amino-3-(2-fluoro-5-iodophenyl)-1-imino-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide was treated with BOC-Anhydride in dichloromethane to give afterchromatography (silica gel, 0% to 100% EtOAc in n-heptane) thefirst-eluting isomer tert-butyl((1R,5R)-5-(2-fluoro-5-iodophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I19A, light brown solid, MS: m/z=510.2 [M+H]⁺) and thesecond-eluting isomer tert-butyl((1S,5R)-5-(2-fluoro-5-iodophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I19B, light brown solid, MS: m/z=510.2 [M+H]⁺)

Intermediate I20A tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 3,tert-butyl((1R,5R)-5-(2-fluoro-5-iodophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1R,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Off-white solid. MS: m/z=480.3 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I3A, step 4,tert-butyl((1R,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with tetrabutylammonium fluoride in dichloromethane.Off-white solid. MS: m/z=408.2 [M+H]⁺.

Intermediate I20B tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

Step 1: In analogy to the synthesis of Intermediate I3A, step 3,tert-butyl((1S,5R)-5-(2-fluoro-5-iodophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1S,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with ethynyltrimethylsilane in THF in the presence ofbis(triphenylphosphine)palladium (II) chloride, copper (I) iodide andtriethylamine. Off-white solid. MS: m/z=480.3 [M+H]⁺.

Step 2: In analogy to the synthesis of Intermediate I3A, step 4,tert-butyl((1S,5R)-5-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with tetrabutylammonium fluoride in dichloromethane.Off-white solid. MS: m/z=408.2 [M+H]⁺.

Experimental Part: Examples Example 1(1S,3S)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: 5-Chloropyrimidine-2-carbonitrile (CAS #38275-56-8, 10 g) andhydroxylamine hydrochloride (5.23 g) were combined in Ethanol (107 ml)and stirred for 5 min. Sodium hydroxide (1M in Water, 72.4 ml) was addedat room temperature. The mixture was stirred for 35 min. The mixture wasdiluted with ice and water. The precipitated solid was collected byfiltration, washed with cold water and dried to give5-chloro-N′-hydroxypyrimidine-2-carboximidamide (10.14 g) as colorlesssolid. MS: m/z=173.0 [M+H]⁺.

Step 2: To a suspension of5-chloro-N′-hydroxypyrimidine-2-carboximidamide (5.05 g) in 3.7M aqueoushydrochloric acid (82.3 ml) a solution of sodium nitrite (2.5 g) inwater (13.2 ml) was added dropwise while stirring at 0° C. The reactionmixture was stirred at 0° C. for 2 h. The suspension was filteredthrough sintered glass, the residue was washed with cold water and driedto give 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride (4.93) asoff-white solid. MS: m/z=192.0 [M+H]⁺.

Step 3: tert-Butyl((1S,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I3A, 77 mg) was dissolved in THF (3.58 ml) at roomtemperature under argon. After addition of5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride (67.3 mg) and sodiumbicarbonate (29.4 mg) the mixture was stirred for 4 days. The mixturewas diluted with ethyl acetate, filtered over a 20 g silica-NH2-column,evaporated and purified by chromatography (silica gel, 0% to 100% EtOAcin n-heptane) to give tert-butyl((1S,5S)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(83 mg) as off-white solid. MS: m/z=593.3 [M−H]⁻.

Step 4:((1S,5S)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(80 mg) was combined under argon with dichloromethane (1 ml).Trifluoroacetic acid (920 mg) was added and the mixture was stirred for2 h. The reaction mixture was evaporated, the residual gum wasevaporated with dichloromethane/n-hexane and 4× with n-hexane and driedto give(1S,3S)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate (81 mg) as colorless solid. MS: m/z=495.1[M+H]⁺.

Example 2(1S,3S)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 2,N′-hydroxy-5-methoxypyrazine-2-carboximidamide (CAS #1344885-60-4) wasconverted to N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride bytreatment with sodium nitrite in water/HCl at 0° C. Off-white solid. MS:m/z=188.3 [M+H]⁺.

Step 2: In analogy to Example 1, step 3, tert-butyl((1S,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I3A) was converted to tert-butyl((1S,5S)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Off-white solid. MS: m/z=589.3[M−H]⁻.

Step 3: In analogy to Example 1, step 4, tert-butyl((1S,5S)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1S,3S)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=491.2 [M+H]⁺.

Example 3(1R,3S)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I3B) was converted to tert-butyl((1R,5S)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Off-white solid. MS: m/z=593.3[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5S)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3S)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=495.1 [M+H]⁺.

Example 4(1R,3S)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine 1-oxide2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 1,5-(2,2-difluoroethoxy)pyrazine-2-carbonitrile (CAS #1544861-08-6) wasconverted to 5-(2,2-difluoroethoxy)-N′-hydroxypyrazine-2-carboximidamideby treatment with hydroxylamine hydrochloride in the presence of aqueoussodium hydroxide. Off-white solid. MS: m/z=219.1 [M+H]⁺.

Step 2: In analogy to Example 1, step 2,5-(2,2-difluoroethoxy)-N′-hydroxypyrazine-2-carboximidamide wasconverted to 5-(2,2-difluoroethoxy)-N-hydroxypyrazine-2-carbimidoylchloride by treatment with sodium nitrite in water/HCl at 0° C. Yellowsolid.

Step 3: In analogy to Example 1, step 3, tert-butyl((1R,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I3B) was converted to tert-butyl((1R,5S)-5-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-(2,2-difluoroethoxy)-N-hydroxypyrazine-2-carbimidoylchloride in the presence of sodium bicarbonate. Off-white solid. MS:m/z=639.3 [M−H]⁻.

Step 4: In analogy to Example 1, step 4, tert-butyl((1R,5S)-5-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3S)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=541.1 [M+H]⁺.

Example 5(1R,3R)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I6A) was converted to tert-butyl((1R,5R)-5-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-(2,2-difluoroethoxy)-N-hydroxypyrazine-2-carbimidoylchloride in the presence of sodium bicarbonate. Colorless solid. MS:m/z=621.4 [M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=523.2 [M+H]⁺.

Example 6(1R,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I6A) was converted to tert-butyl((1R,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=575.3[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=477.1 [M+H]⁺.

Example 7(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I6A) was converted to tert-butyl((1R,5R)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=575.3[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=473.2 [M+H]⁺.

Example 82-(5-(3-((1R,3R)-5-amino-3,6,6-trimethyl-1-(methylimino)-1-oxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)isoxazol-3-yl)pyrimidine-5-carbonitrile2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 1, pyrimidine-2,5-dicarbonitrile(CAS #38275-58-0) was converted to5-cyano-N′-hydroxypyrimidine-2-carboximidamide by treatment withhydroxylamine hydrochloride in the presence of aqueous sodium hydroxide.Light brown solid. MS: m/z=164.057 [M+H]+.

Step 2: In analogy to Example 1, step 2,5-cyano-N′-hydroxypyrimidine-2-carboximidamide was converted to5-cyano-N-hydroxypyrimidine-2-carbimidoyl chloride by treatment withsodium nitrite in water/HCl at 0° C. Off-white solid.

Step 3: In analogy to Example 1, step 3, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I6A) was converted to tert-butyl((1R,5R)-5-(5-(3-(5-cyanopyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-cyano-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=566.3[M−H]⁻.

Step 4: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(5-(3-(5-cyanopyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to2-(5-(3-((1R,3R)-5-amino-3,6,6-trimethyl-1-(methylimino)-1-oxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)isoxazol-3-yl)pyrimidine-5-carbonitrile2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=468.2 [M+H]⁺.

Example 9(1R,3R)-5-amino-3-(5-(1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: tert-Butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I6A, 50 mg) and 2-azido-5-chloropyridine (CAS#242815-95-8, 18.3 mg) were mixed under argon with toluene (1.5 ml).After addition of copper(I) trifluoromethanesulfonate benzene complex(5.97 mg) the reaction mixture was stirred for 2 days at rt in a scaledtube. The mixture was diluted with ethyl acetate, filtered through aglass fiber filter, evaporated and purified by chromatography (silicagel, 0% to 80% EtOAc in n-heptane) to give tert-butyl((1R,5R)-5-(5-(1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(49.8 mg) as colorless solid. MS: m/z=574.4 [M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(5-(1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-5-amino-3-(5-(1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=476.1 [M+H]⁺.

Example 106-(4-(3-((1R,3R)-5-amino-3,6,6-trimethyl-1-(methylimino)-1-oxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile2,2,2-trifluoroacetate

Step 1: In analogy to Example 9, step 1, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I6A) was converted to tert-butyl((1R,5R)-5-(5-(1-(5-cyanopyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 6-azidonicotinonitrile (CAS #1139703-59-5) in thepresence of copper(I) trifluoromethanesulfonate benzene complex.Colorless solid. MS: m/z=467.2 [M+H-BOC]⁺.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(5-(1-(5-cyanopyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to6-(4-(3-((1R,3R)-5-amino-3,6,6-trimethyl-1-(methylimino)-1-oxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Colorless solid. MS: m/z=467.1 [M+H]⁺.

Example 11(1S,3R)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I6B) was converted to tert-butyl((1S,5R)-5-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-(2,2-difluoroethoxy)-N-hydroxypyrazine-2-carbimidoylchloride in the presence of sodium bicarbonate. Colorless solid. MS:m/z=621.3 [M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1S,5R)-5-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1S,3R)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=523.2 [M+H]⁺.

Example 12(1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I6B) was converted to tert-butyl((1S,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=575.2[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1S,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Colorless solid. MS: m/z=477.1 [M+H]⁺.

Example 13(1S,3S)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide

Step 1: In analogy to Example 1, step 2,N′-hydroxy-5-methoxypyrimidine-2-carboximidamide (CAS #143031-89-4) wasconverted to N-hydroxy-5-methoxypyrimidine-2-carbimidoyl chloride bytreatment with sodium nitrite in water/HCl at 0° C. Off-white solid. MS:m/z=188.1 [M+H]⁺.

Step 2: In analogy to Example 1, step 3, tert-butyl((1S,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I3A) was converted to tert-butyl((1S,5S)-5-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with N-hydroxy-5-methoxypyrimidine-2-carbimidoyl chloridein the presence of sodium bicarbonate. Colorless solid. MS: m/z=589.3[M−H]⁻.

Step 3: In analogy to Example 1, step 4, tert-butyl((1S,5S)-5-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1S,3S)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with trifluoroacetic acid in dichloromethane.Off-white solid. MS: m/z=491.2 [M+H]⁻.

Example 146-(4-(3-((1R,3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-1-oxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-1H-1,2,3-triazol-L-yl)nicotinonitrile2,2,2-trifluoroacetate

Step 1: In analogy to Example 9, step 1, tert-butyl((1R,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I3B) was converted to tert-butyl((1R,5S)-5-(5-(1-(5-cyanopyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 6-azidonicotinonitrile (CAS #1139703-59-5) in thepresence of copper(I) trifluoromethanesulfonate benzene complex.Colorless solid. MS: m/z=585.2 [M+H]⁺.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5S)-5-(5-(1-(5-cyanopyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to6-(4-(3-((1R,3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-1-oxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Colorless solid. MS: m/z=485.2 [M+H]⁺.

Example 15(1R,3S)-5-amino-3-(5-(3-(5-bromo-3-methylpyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 1, 5-bromo-3-methylpicolinonitrile(CAS #156072-86-5) was converted to5-bromo-N′-hydroxy-3-methylpicolinimidamide by treatment withhydroxylamine hydrochloride in the presence of aqueous sodium hydroxide.Off-white solid. MS: m/z=230.0 [M+H]⁺.

Step 2: In analogy to Example 1, step 2,5-bromo-N′-hydroxy-3-methylpicolinimidamide was converted to5-bromo-N-hydroxy-3-methylpicolinimidoyl chloride by treatment withsodium nitrite in water/HCl at 0° C. Off-white solid.

Step 3: In analogy to Example 1, step 3, tert-butyl((1R,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I3B) was converted to tert-butyl((1R,5S)-5-(5-(3-(5-bromo-3-methylpyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-bromo-N-hydroxy-3-methylpicolinimidoyl chloride inthe presence of sodium bicarbonate. Off-white solid. MS: m/z=652.4[M−H]⁻.

Step 4: In analogy to Example 1, step 4, tert-butyl((1R,5S)-5-(5-(3-(5-bromo-3-methylpyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3S)-5-amino-3-(5-(3-(5-bromo-3-methylpyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=554.1 [M+H]⁺.

Example 16(1R,3S)-5-amino-3-(5-(1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 9, step 1, tert-butyl((1R,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I3B) was converted to tert-butyl((1R,5S)-5-(5-(1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 2-azido-5-chloropyridine (CAS #242815-95-8) in thepresence of copper(I) trifluoromethanesulfonate benzene complex.Colorless solid. MS: m/z=594.2 [M+H]⁺.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5S)-5-(5-(1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3S)-5-amino-3-(5-(1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=494.2 [M+H]⁺.

Example 17(1R,3S)-3-[2-fluoro-5-[3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl]phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5S)-5-(5-ethynyl-2-fluorophenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I3B) was converted to tert-butyl((1R,5S)-5-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with N-hydroxy-5-methoxypyrimidine-2-carbimidoyl chloridein the presence of sodium bicarbonate. Light yellow solid. MS: m/z=589.3[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5S)-5-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-5-(fluoromethyl)-2,2-dimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3S)-3-[2-fluoro-5-[3-(5-methoxypyrimidin-2-yl)-1,2-oxazol-5-yl]phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amineby treatment with trifluoroacetic acid in dichloromethane followed bychromatography over amino-modified silica gel. Colorless solid. MS:m/z=491.2 [M+H]⁺.

Example 18(1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine

Step 1: To a solution of 2-(methylthio)pyrimidin-5-ol (CAS #4874-33-3, 2g) in acetone (50 ml) were added potassium carbonate (2.92 μg) and2,2-difluoroethyl trifluoromethanesulfonate (3.46 g) and the mixture wasstirred for 3 h at room temperature. Diethyl ether (200 ml) was addedand the mixture was filtered. The filtrate was concentrated and thecrude material was purified by flash chromatography (silica gel, 0% to50% EtOAc in n-heptane) to give5-(2,2-difluoroethoxy)-2-(methylthio)pyrimidine (2.65 g) as light yellowsolid. MS: m/z=207.0 [M+H]⁺.

Step 2: 5-(2,2-Difluoroethoxy)-2-(methylthio)pyrimidine (2.46 g) wasdissolved in dichloromethane (45 ml). After addition of3-chloroperbenzoic acid (8.02 g) the mixture was stirred for 90 min atroom temperature. The mixture was diluted with dichloromethane, washedwith aqueous saturated sodium carbonate solution and with water. Theorganic layer was dried over sodium sulphate and concentrated. The crudeproduct was purified by filtration with dichloromethane through a 50 gsilica-NH2 column to give5-(2,2-difluoroethoxy)-2-(methylsulfonyl)pyrimidine (2.73 g) ascolorless solid. MS: m/z=239.1 [M+H]⁺.

Step 3: 5-(2,2-Difluoroethoxy)-2-(methylsulfonyl)pyrimidine (2.31 g) wasdissolved in dichloromethane (26.4 ml). After addition oftetrabutylammonium cyanide (3.25 g) the mixture was stirred for 18 h atroom temperature. The mixture was evaporated to a smaller volume anddirectly purified by chromatography (silica gel, dichloromethane) togive 5-(2,2-difluoroethoxy)pyrimidine-2-carbonitrile (2.19 g) as lightyellow liquid.

Step 4: In analogy to Example 1, step 1,5-(2,2-difluoroethoxy)pyrimidine-2-carbonitrile was converted to5-(2,2-difluoroethoxy)-N′-hydroxypyrimidine-2-carboximidamide bytreatment with hydroxylamine hydrochloride in the presence of aqueoussodium hydroxide. Colorless solid. MS: m/z=219.1 [M+H]⁺.

Step 5: In analogy to Example 1, step 2,5-(2,2-difluoroethoxy)-N′-hydroxypyrimidine-2-carboximidamide wasconverted to 5-(2,2-difluoroethoxy)-N-hydroxypyrimidine-2-carbimidoylchloride by treatment with sodium nitrite in water/HCl at 0° C.Colorless solid.

Step 6: 1-(2-Fluoro-5-hydroxyphenyl)ethanone (6.17 g) and pyridine (6.33g) were combined with dichloromethane (60 ml) and cooled in an ice bath.Trifluoromethanesulfonic anhydride (13.5 g) was added dropwise. After 15min the ice bath was removed and the mixture was stirred at roomtemperature for 1 h. The mixture was again cooled in an ice bath andquenched by addition of sat. NaHCO₃ solution and water. The org. phasewas separated, washed with water, dried (MgSO₄) and filtered. Thefiltrate was concentrated to dryness and dried to give3-acetyl-4-fluorophenyl trifluoromethanesulfonate as a light brownliquid. (11.17 g)

Step 7: A solution of 3-acetyl-4-fluorophenyl trifluoromethanesulfonate(5.018 g) in N,N-dimethylformamide (30 ml) and triethylamine (10.9 g)was purged with argon for 10 min. copper (I) iodide (334 mg),trimethylsilylacetylene (3.44 μg) and bis(triphenylphosphine)palladium(II) chloride (615 mg) were added and the mixture was heated to 80° C.for 110 min. After cooling to room temperature, water was added and themixture was extracted with EtOAc. The organic layers were dried (MgSO₄),filtered over a plug of SiO₂ and concentrated in vacuo. The crudematerial was purified by flash chromatography (SiO₂, 0% to 30% EtOAc inn-heptane) to give1-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)ethanone (4.08 g) as lightbrown liquid.

Step 8: 1-(2-fluoro-5-((trimethylsilyl)ethynyl)phenyl)ethanone (1 g) wasdissolved in dichloromethane (60.1 ml) under argon and cooled to 0° C.After addition of TBAF, (1M in THF, 4.69 ml) the mixture was stirred for85 min at 0° C. The mixture was diluted with dichloromethane and washedwith water, The combined org. layers were dried over sodium sulphate andconcentrated. The crude material was purified by flash chromatography(SiO₂, 0% to 50% EtOAc in n-heptane) to give1-(5-ethynyl-2-fluorophenyl)ethanone as light yellow solid (590 mg).

Step 9: In analogy to Example 1, step 3,1-(5-ethynyl-2-fluorophenyl)ethanone was converted to1-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)ethanoneby treatment with5-(2,2-difluoroethoxy)-N-hydroxypyrimidine-2-carbimidoyl chloride in thepresence of sodium bicarbonate. Light yellow solid. MS: m/z=364.1[M+H]⁺.

Step 10:1-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)ethanone(1.15 g) and (R)-(+)-2-methyl-2-propanesulfinamide (767 mg) weredissolved under argon in THF (6.42 ml). After addition of titanium(iv)ethoxide (1.44 g) the reaction mixture was stirred at for 3 weeks. Afteraddition of 0.5 ml water, 25 ml ethyl acetate and Dicalite, the mixturewas stirred for 10 min, filtered and rinsed well with ethyl acetate. Thefiltrate was concentrated and purified by chromatography (SiO₂, 0% to100% EtOAc in n-heptane) to give(R)—N-(1-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide(305 mg) as off-white solid. MS: m/z=467.2 [M+H]⁺.

Step 11: In analogy to the synthesis of Intermediate I1A, step 1,(R)—N-(1-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamidewas converted to(R)—N-((2R)-1-(2-cyano-N-methylpropan-2-ylsulfonimidoyl)-2-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamideby treatment with 2-(N,S-dimethylsulfonimidoyl)-2-methylpropanenitrile(pre-treated with lithium bis(trimethylsilyl)amide). Light yellow solid.MS: m/z=627.1 [M+H]⁺.

Step 12: In analogy to the synthesis of Intermediate I1A, step 2,(R)—N-((2R)-1-(2-cyano-N-methylpropan-2-ylsulfonimidoyl)-2-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)propan-2-yl)-2-methylpropane-2-sulfinamidewas reacted with HCl in dioxane/methanol to give after chromatography(SiO₂, 0% to 100% EtOAc in n-heptane)2-((2R)-2-amino-2-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrile(first-eluting isomer, off-white solid, MS: m/z=523.2 [M+H]⁺) and2-((2R)-2-amino-2-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrile(second-eluting isomer, off-white solid, MS: m/z=523.2 [M+H]⁺).

Step 13: In analogy to the synthesis of Intermediate I2A, step 1,2-((2R)-2-amino-2-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrilewas treated with copper (I) chloride to give(1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]-1,2-oxazol-5-yl]-2-fluorophenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amineas off-white solid, MS: m/z=523.2 [M+H]⁺.

Example 19(1S,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine

Step 1: In analogy to the synthesis of Intermediate I2A, step 1,2-((2R)-2-amino-2-(5-(3-(5-(2,2-difluoroethoxy)pyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-N-methylpropylsulfonimidoyl)-2-methylpropanenitrilewas treated with copper (I) chloride to give(1S,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]-1,2-oxazol-5-yl]-2-fluorophenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amineas off-white solid, MS: m/z=523.2 [M+H]⁺.

Example 20(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I6A) was converted to tert-butyl((1R,5R)-5-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with N-hydroxy-5-methoxypyrimidine-2-carbimidoyl chloridein the presence of sodium bicarbonate. The product could not be obtainedpure and was used directly for the next step.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with trifluoroacetic acid in dichloromethane.Colorless solid. MS: m/z=473.2 [M+H]⁺.

Example 21(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 2,N′-hydroxy-5-(2,2,2-trifluoroethoxy)pyrazine-2-carboximidamide (CAS#1344794-41-7) was converted toN-hydroxy-5-(2,2,2-trifluoroethoxy)pyrazine-2-carbimidoyl chloride bytreatment with sodium nitrite in water/HCl at 0° C. Off-white solid.

Step 2: In analogy to Example 1, step 3, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I6A) was converted to tert-butyl((1R,5R)-5-(2-fluoro-5-(3-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment withN-hydroxy-5-(2,2,2-trifluoroethoxy)pyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=639.4[M−H]⁻.

Step 3: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(2-fluoro-5-(3-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=541.2 [M+H]⁺.

Example 22(1R,3R)-5-amino-3-(5-(3-(5-(cyclopropylmethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide

Step 1: In analogy to Example 1, step 2,5-(cyclopropylmethoxy)-N′-hydroxypyrazine-2-carboximidamide (CAS#1344867-87-3) was converted to5-(cyclopropylmethoxy)-N-hydroxypyrazine-2-carbimidoyl chloride bytreatment with sodium nitrite in water/HCl at 0° C. Off-white solid.

Step 2: In analogy to Example 1, step 3, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I6A) was converted to tert-butyl((1R,5R)-5-(5-(3-(5-(cyclopropylmethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-(cyclopropylmethoxy)-N-hydroxypyrazine-2-carbimidoylchloride in the presence of sodium bicarbonate. Colorless solid. MS:m/z=611.4 [M−H]⁻.

Step 3: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(5-(3-(5-(cyclopropylmethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-(methylimino)-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-5-amino-3-(5-(3-(5-(cyclopropylmethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with trifluoroacetic acid in dichloromethane.Off-white solid. MS: m/z=513.3 [M+H]⁺.

Example 23(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-hydroxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide

As a side product in the formation of Example 22, step 3,(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-hydroxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide was isolated as off-white solid. MS: m/z=459.2 [M+H]⁺.

Example 24(1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butylN-[(1R,3R)-3-(5-ethynyl-2-fluoro-phenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamate(Intermediate I9A) was converted to tert-butylN-[(1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamateby treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=576.3[M+H]⁺.

Step 2: In analogy to Example 1, step 4, tert-butylN-[(1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamatewas converted to(1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)-1,2-oxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=476.3 [M+H]⁺.

Example 25(1R,3R)-3-[2-fluoro-5-[3-[5-(2,2,3,3-tetrafluoropropoxy)pyrimidin-2-yl]isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate

Step 1: 2-Chloropyrimidin-5-ol (5.3 g) was dissolved under argon inacetone (144 ml). After addition of potassium carbonate (8.42 μg) and2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate (12.3 g) the mixturewas stirred for 18 h. The mixture was diluted with ˜200 ml ether,stirred for 10 min and filtered. The filtrate was concentrated, taken upin dichloromethane, filtered again and concentrated to dryness to give2-chloro-5-(2,2,3,3-tetrafluoropropoxy)pyrimidine (8.99 g, not totallypure) as orange oil. MS: m/z=245.0 [M+H]⁺.

Step 2: 2-Chloro-5-(2,2,3,3-tetrafluoropropoxy)pyrimidine (1.5 g) wasdissolved in N,N-dimethylacetamide (25 ml). After addition of zinccyanide (864 mg) and tetrakis-triphenylphosphin-palladium (709 mg) themixture was stirred for 45 min at 160° C. under argon.

The mixture was diluted with water, stirred for 5 min and filtered. Thefiltrate was extracted with EtOAc, the organic layers were washed withwater, combined, dried over sodium sulphate and concentrated. The crudematerial was purified by flash chromatography (silica gel, 0% to 30%EtOAc in n-heptane) to give5-(2,2,3,3-tetrafluoropropoxy)pyrimidine-2-carbonitrile (944 mg) ascolorless oil. MS: m/z=236.1 [M+H]⁺.

Step 3: In analogy to Example 1, step 1,5-(2,2,3,3-tetrafluoropropoxy)pyrimidine-2-carbonitrile was converted toN′-hydroxy-5-(2,2,3,3-tetrafluoropropoxy)pyrimidine-2-carboximidamide bytreatment with hydroxylamine hydrochloride in the presence of aqueoussodium hydroxide. Colorless solid. MS: m/z=269.1 [M+H]⁺.

Step 4: In analogy to Example 1, step 2,N′-hydroxy-5-(2,2,3,3-tetrafluoropropoxy)pyrimidine-2-carboximidamidewas converted toN-hydroxy-5-(2,2,3,3-tetrafluoropropoxy)pyrimidine-2-carbimidoylchloride by treatment with sodium nitrite in water/HCl at 0° C.Colorless solid.

Step 5: In analogy to Example 1, step 3, tert-butylN-[(1R,3R)-3-(5-ethynyl-2-fluoro-phenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamate(Intermediate I9A) was converted to tert-butylN-[(1R,3R)-3-[2-fluoro-5-[3-[5-(2,2,3,3-tetrafluoropropoxy)pyrimidin-2-yl]-1,2-oxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamateby treatment withN-hydroxy-5-(2,2,3,3-tetrafluoropropoxy)pyrimidine-2-carbimidoylchloride in the presence of sodium bicarbonate. Colorless solid. MS:m/z=674.5 [M−H]⁻.

Step 6: In analogy to Example 1, step 4, tert-butylN-[(1R,3R)-3-[2-fluoro-5-[3-[5-(2,2,3,3-tetrafluoropropoxy)pyrimidin-2-yl]-1,2-oxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamatewas converted to(1R,3R)-3-[2-fluoro-5-[3-[5-(2,2,3,3-tetrafluoropropoxy)pyrimidin-2-yl]-1,2-oxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=576.3 [M+H]⁺.

Example 26(1R,3R)-3-[5-[3-(5-ethylpyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 1,5-ethylpyrimidine-2-carbonitrile (CAS #1622073-68-0) was converted to5-ethyl-N′-hydroxypyrimidine-2-carboximidamide by treatment withhydroxylamine hydrochloride in the presence of aqueous sodium hydroxide.Off-white solid. MS: m/z=167.1 [M+H]⁺.

Step 2: In analogy to Example 1, step 2,5-ethyl-N′-hydroxypyrimidine-2-carboximidamide was converted to5-ethyl-N-hydroxypyrimidine-2-carbimidoyl chloride by treatment withsodium nitrite in water/HCl at 0° C. Colorless solid. MS: m/z=186.1[M+H]⁺.

Step 3: In analogy to Example 1, step 3, tert-butylN-[(1R,3R)-3-(5-ethynyl-2-fluoro-phenyl)-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamate(Intermediate I9A) was converted to tert-butylN-[(1R,3R)-3-[5-[3-(5-ethylpyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamateby treatment with 5-ethyl-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Off-white solid. MS: m/z=572.5[M−H]⁻.

Step 4: In analogy to Example 1, step 4, tert-butylN-[(1R,3R)-3-[5-[3-(5-ethylpyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-yl]carbamatewas convertedto(1R,3R)-3-[5-[3-(5-ethylpyrimidin-2-yl)-1,2-oxazol-5-yl]-2-fluorophenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=474.4 [M+H]⁺.

Example 27

(6R,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate Step 1: In analogy to Example 1, step 3,tert-butyl((6R,8R)-8-(5-ethynyl-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamate(Intermediate I12A) was converted to tert-butyl((6R,8R)-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=599.3[M+H]⁺.

Step 2: In analogy to Example 1, step 4, tert-butyl((6R,8R)-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamatewas converted to(6R,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Light yellow solid. MS: m/z=499.3 [M+H]⁺.

Example 28(6R,8R)-10-amino-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((6R,8R)-8-(5-ethynyl-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamate(Intermediate I12A) was converted to tert-butyl((6R,8R)-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=603.3[M+H]⁺.

Step 2: In analogy to Example 1, step 4, tert-butyl((6R,8R)-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamatewas converted to(6R,8R)-10-amino-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Colorless solid. MS: m/z=503.2 [M+H]⁺.

Example 29(6R,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((6R,8R)-8-(5-ethynyl-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamate(Intermediate I12A) was converted to tert-butyl((6R,8R)-8-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with N-hydroxy-5-methoxypyrimidine-2-carbimidoyl chloridein the presence of sodium bicarbonate. Light yellow solid. MS: m/z=599.4[M+H]⁺.

Step 2: In analogy to Example 1, step 4, tert-butyl((6R,8R)-8-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamatewas converted to(6R,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Light yellow solid. MS: m/z=499.3 [M+H]⁺.

Example 30(6R,8R)-10-amino-8-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide

Step 1: In analogy to Example 1, step 3, tert-butyl((6R,8R)-8-(5-ethynyl-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamate(Intermediate I12A) was converted to tert-butyl((6R,8R)-8-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with 5-(2,2-difluoroethoxy)-N-hydroxypyrazine-2-carbimidoylchloride in the presence of sodium bicarbonate. The product was notobtained pure and was used directly for the next step.

Step 2: In analogy to Example 1, step 4, tert-butyl((6R,8R)-8-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamatewas converted to(6R,8R)-10-amino-8-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide by treatment with trifluoroacetic acid in dichloromethane.Off-white solid. MS: m/z=549.3 [M+H]⁺.

Example 31(6S,8R)-10-amino-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((6S,8R)-8-(5-ethynyl-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamate(Intermediate I12B) was converted to tert-butyl((6S,8R)-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=601.5[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((6S,8R)-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamatewas converted to(6S,8R)-10-amino-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Colorless solid. MS: m/z=503.3 [M+H]⁺.

Example 32(6S,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((6S,8R)-8-(5-ethynyl-2-fluorophenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamate(Intermediate I12B) was converted to tert-butyl((6S,8R)-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamateby treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=599.3[M+H]⁺.

Step 2: In analogy to Example 1, step 4, tert-butyl((6S,8R)-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-oxido-6-thia-9-azaspiro[4.5]dec-9-en-10-yl)carbamatewas converted to(6S,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Colorless solid. MS: m/z=499.3 [M+H]⁺.

Example 33(1R,3R)-5-amino-1-(cyclopropylimino)-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5R)-1-(cyclopropylimino)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I15A) was converted to tert-butyl((1R,5R)-1-(cyclopropylimino)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=599.5[M+H]⁺.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-1-(cyclopropylimino)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-5-amino-1-(cyclopropylimino)-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with trifluoroacetic acid in dichloromethane.Colorless solid. MS: m/z=499.4 [M+H]⁺.

Example 34(1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-1-cyclopropylimino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5R)-1-(cyclopropylimino)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I15A) was converted to tert-butyl((1R,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-(cyclopropylimino)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Off-white solid. MS: m/z=601.7[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-(cyclopropylimino)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)-1,2-oxazol-5-yl]-2-fluorophenyl]-1-cyclopropylimino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine;2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Colorless solid. MS: m/z=503.4 [M+H]⁺.

Example 35(1S,3R)-5-amino-1-(cyclopropylimino)-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1S,5R)-1-(cyclopropylimino)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I15B) was converted to tert-butyl((1S,5R)-1-(cyclopropylimino)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=599.5[M+H]⁺.

Step 2: In analogy to Example 1, step 4, tert-butyl((1S,5R)-1-(cyclopropylimino)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1S,3R)-5-amino-1-(cyclopropylimino)-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Colorless solid. MS: m/z=499.4 [M+H]⁺.

Example 36(1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-(cyclopropylimino)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1S,5R)-1-(cyclopropylimino)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I15B) was converted to tert-butyl((1S,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-(cyclopropylimino)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=601.7[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1S,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-(cyclopropylimino)-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-(cyclopropylimino)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Colorless solid. MS: m/z=503.4 [M+H]⁺.

Example 37(1S,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate

(Intermediate I18A) was converted to tert-butyl((1S,5R)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=639.3[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1S,5R)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1S,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=541.2 [M+H]⁺.

Example 38(1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I18A) was converted to tert-butyl((1S,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=643.3[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1S,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Colorless solid. MS: m/z=545.1 [M+H]⁺.

Example 39(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I18B) was converted to tert-butyl((1R,5R)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=639.4[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-2,2,5-triethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Colorless solid. MS: m/z=541.2 [M+H]⁺.

Example 40(1R,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I18B) was converted to tert-butyl((1R,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Colorless solid. MS: m/z=643.3[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-2,2,5-trimethyl-1-oxido-1-((2,2,2-trifluoroethyl)imino)-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=545.2 [M+H]⁺.

Example 41(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-1-imino-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I20A) was converted to tert-butyl((1R,5R)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Off-white solid. MS: m/z=559.3[M+H]^(|).

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-1-imino-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide by treatment with trifluoroacetic acid in dichloromethane.Off-white solid. MS: m/z=459.3 [M+H]⁺.

Example 42(1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine;2,2,2-trifluoroacetic acid 2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1R,5R)-5-(5-ethynyl-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I20A) was converted to tert-butyl((1R,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Off-white solid. MS: m/z=561.5[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1R,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)-1,2-oxazol-5-yl]-2-fluorophenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=463.3 [M+H]⁺.

Example 43(1S,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I20B) was converted to tert-butyl((1S,5R)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with N-hydroxy-5-methoxypyrazine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Off-white solid. MS: m/z=557.5[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1S,5R)-5-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1S,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)-1,2-oxazol-5-yl]phenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=459.3 [M+H]⁺.

Example 44(1S,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate

Step 1: In analogy to Example 1, step 3, tert-butyl((1S,5R)-5-(5-ethynyl-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamate(Intermediate I20B) was converted to tert-butyl((1S,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamateby treatment with 5-chloro-N-hydroxypyrimidine-2-carbimidoyl chloride inthe presence of sodium bicarbonate. Off-white solid. MS: m/z=561.5[M−H]⁻.

Step 2: In analogy to Example 1, step 4, tert-butyl((1S,5R)-5-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-imino-2,2,5-trimethyl-1-oxido-5,6-dihydro-2H-1,4-thiazin-3-yl)carbamatewas converted to(1S,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)-1,2-oxazol-5-yl]-2-fluorophenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate by treatment with trifluoroacetic acid indichloromethane. Off-white solid. MS: m/z=463.3 [M+H]⁺.

1. A compound of formula I,

A is a heteroaryl group, B is a heteroaryl group, R¹ is selected fromthe group consisting of i) C₁₋₆-alkyl and ii) halogen-C₁₋₆-alkyl; R² isselected from the group consisting of i) C₁₋₆-alkyl, and ii)halogen-C₁₋₆-alkyl; or R¹ and R² form together with the C-atom they areattached to, a C₃₋₆-cycloalkyl-, wherein the C₃₋₆-cycloalkyl- isoptionally substituted by one or more substituents selected from thegroup consisting of halogen and hydroxyl; R³ is selected from the groupconsisting of i) hydrogen, ii) C₃₋₆-cycloalkyl, iii) halogen-C₁₋₆-alkyl,and iv) C₁₋₆-alkyl; R⁴ is selected from the group consisting of i)hydrogen, and ii) C₁₋₆-alkyl; R⁵ is selected from the group consistingof i) C₁₋₆-alkyl, and ii) halogen-C₁₋₆-alkyl; R⁶ is halogen; R⁷ isselected from the group consisting of i) amino, ii) cyano, iii)hydrogen, iv) OH, v) halogen, vi) C₁₋₆-alkyl, vii)C₁₋₆-alkyl-C₃₋₆-cycloalkyl, viii) halogen-C₁₋₆-alkyl, ix)C₁₋₆-alkoxy-C₁₋₆-alkyl, x) C₂₋₆-alkynyl, xi) C₂₋₆-alkynyl-C₁₋₆-alkyl,xii) C₂₋₆-alkynyl-C₁₋₆-alkoxy xiii) C₁₋₆-alkoxy, and xiv)halogen-C₁₋₆-alkoxy; or pharmaceutically acceptable salts thereof.
 2. Acompound of formula I according to claim 1, wherein A is a heteroarylgroup, B is a heteroaryl group, R¹ is selected from the group consistingof i) C₁₋₆-alkyl and ii) halogen-C₁₋₆-alkyl; R² is selected from thegroup consisting of i) C₁₋₆-alkyl, and ii) halogen-C₁₋₆-alkyl; or R¹ andR² form together with the C-atom they are attached to aC₃₋₆-cycloalkyl-, wherein the C₃₋₆-cycloalkyl- is optionally substitutedby one or more substituents selected from the group consisting ofhalogen and hydroxyl; R³ is selected from the group consisting of i)hydrogen, ii) halogen-C₁₋₆-alkyl, and iii) C₁₋₆-alkyl; R⁴ is selectedfrom the group consisting of i) hydrogen, and ii) C₁₋₆-alkyl; R⁵ isselected from the group consisting of i) C₁₋₆-alkyl, and ii)halogen-C₁₋₆-alkyl; R⁶ is halogen; R⁷ is selected from the groupconsisting of i) amino, ii) cyano, iii) hydrogen, iv) halogen, v)C₁₋₆-alkyl, vi) halogen-C₁₋₆-alkyl, vii) C₁₋₆-alkoxy-C₁₋₆-alkyl, viii)C₂₋₆-alkynyl, ix) C₂₋₆-alkynyl-C₁₋₆-alkyl, x) C₂₋₆-alkynyl-C₁₋₆-alkoxyxi) C₁₋₆-alkoxy, and xii) halogen-C₁₋₆-alkoxy; or pharmaceuticallyacceptable salts thereof.
 3. A compound of formula I according to anyone of claim 1 or 2, which is of formula Ia, wherein A, B, R¹, R², R³,R⁴, R⁵, R⁶ and R⁷ is as defined in any one of claim 1 or 2


4. A compound of formula T according to any one of claims 1-3, wherein Ais a 5-membered heteroaryl group.
 5. A compound of formula I accordingto any one of claims 1-4, wherein A is isoxazolyl or triazolyl.
 6. Acompound of formula I according to any one of claims 1-5, wherein B is a6-membered heteroaryl group.
 7. A compound of formula I according to anyone of claims 1-5, wherein B is pyrazinyl, pyrimidinyl or pyridinyl. 8.A compound of formula I according to any one of claims 1-7, wherein R¹is C₁₋₆-alkyl.
 9. A compound of formula I according to any one of claims1-8, wherein R¹ is methyl.
 10. A compound of formula I according to anyone of claims 1-9, wherein R² is C₁₋₆-alkyl.
 11. A compound of formula Iaccording to any one of claims 1-10, wherein R² is methyl.
 12. Acompound of formula I according to any one of claims 1-7, wherein R¹ andR² form together with the C-atom they are attached to aC₃₋₆-cycloalkyl-.
 13. A compound of formula I according to any one ofclaims 1-7 or 12, wherein R¹ and R² form together with the C-atom theyare attached to a cyclopentyl.
 14. A compound of formula I according toany one of claims 1-13, wherein R³ is H, CH₃, CD₃, CH₂CF₃ orcyclopropyl.
 15. A compound of formula I according to any one of claims1-13, wherein R³ is C₁₋₆-alkyl.
 16. A compound of formula I according toany one of claims 1-15, wherein R³ is methyl.
 17. A compound of formulaI according to any one of claims 1-16, wherein R⁴ is hydrogen.
 18. Acompound of formula I according to any one of claims 1-17, wherein R⁵ isC₁₋₆-alkyl or halogen-C₁₋₆-alkyl.
 19. A compound of formula I accordingto any one of claims 1-18, wherein R⁵ is methyl or —CH₂F.
 20. A compoundof formula I according to any one of claims 1-19, wherein R⁶ is F.
 21. Acompound of formula I according to any one of claims 1-20, wherein R⁷ isBr, CH₂-cyclopropyl, Cl, CN, Et, Me, OCH₂CF₂CHF₂, OCH₂CF₃, OCH₂CHF₂, OHor OMe.
 22. A compound of formula I according to any one of claims 1-21that is selected from the group consisting of(1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;2,2,2-trifluoroacetic acid,(1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate,(1R,3R)-3-[2-fluoro-5-[3-[5-(2,2,3,3-tetrafluoropropoxy)pyrimidin-2-yl]isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate,(1R,3R)-3-[5-[1-(5-chloro-2-pyridyl)triazol-4-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;2,2,2-trifluoroacetic acid,(1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;2,2,2-trifluoroacetic acid,(1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-1-cyclopropylimino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate,(1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine;2,2,2-tri fluoroacetic acid 2,2,2-trifluoroacetate,(1R,3R)-3-[5-[3-(5-ethylpyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-oxo-1-(trideuteriomethylimino)-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate,(1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrazin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;2,2,2-trifluoroacetic acid,(1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine,(1R,3R)-5-amino-1-(cyclopropylimino)-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide,(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-hydroxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide,(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-1-imino-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide,(1R,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide,(1R,3R)-5-amino-3-(5-(3-(5-(cyclopropylmethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide,(1R,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1R,3S)-3-[2-fluoro-5-[3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl]phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine,(1R,3S)-5-amino-3-(5-(1-(5-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1R,3S)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1R,3S)-5-amino-3-(5-(3-(5-bromo-3-methylpyridin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1R,3S)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1S,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate,(1S,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-1-imino-3,6,6-trimethyl-1-oxo-2H-1,4-thiazin-5-amine2,2,2-trifluoroacetate,(1S,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrimidin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine,(1S,3R)-5-amino-1-(cyclopropylimino)-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1S,3R)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1S,3R)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-1-(cyclopropylimino)-3,6,6-trimethyl-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-((2,2,2-trifluoroethyl)imino)-3,6-dihydro-2H-1,4-thiazine1-oxide 2,2,2-trifluoroacetate,(1S,3S)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;2,2,2-trifluoroacetic acid,(1S,3S)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-amine;2,2,2-trifluoroacetic acid,(1S,3S)-5-amino-3-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide,(6R,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate,(6R,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrimidin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate,(6R,8R)-10-amino-8-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide,(6R,8R)-10-amino-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate,(6S,8R)-10-amino-8-(2-fluoro-5-(3-(5-methoxypyrazin-2-yl)isoxazol-5-yl)phenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate,(6S,8R)-10-amino-8-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-8-methyl-6-(methylimino)-6-thia-9-azaspiro[4.5]dec-9-ene6-oxide 2,2,2-trifluoroacetate,2-[5-[3-[(1R,3R)-5-amino-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-3-yl]-4-fluoro-phenyl]isoxazol-3-yl]pyrimidine-5-carbonitrile;2,2,2-trifluoroacetic acid,6-(4-(3-((1R,3S)-5-amino-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-1-oxido-3,6-dihydro-2H-1,4-thiazin-3-yl)-4-fluorophenyl)-1H-1,2,3-triazol-1-yl)nicotinonitrile2,2,2-trifluoroacetate, and6-[4-[3-[(1R,3R)-5-amino-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-3-yl]-4-fluoro-phenyl]triazol-1-yl]pyridine-3-carbonitrile2,2,2-trifluoroacetic acid.
 23. A compound of formula I according to anyone of claims 1-22 that is selected from the group consisting of(1R,3R)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-aminetrifluoroacetate,(1R,3R)-3-[5-[1-(5-chloro-2-pyridyl)triazol-4-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-aminetrifluoroacetate,(1R,3R)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-aminetrifluoroacetate,(1R,3R)-3-[5-[3-[5-(2,2-difluoroethoxy)pyrazin-2-yl]isoxazol-5-yl]-2-fluoro-phenyl]-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-aminetrifluoroacetate,(1R,3S)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide trifluoroacetate,(1R,3S)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3-(fluoromethyl)-6,6-dimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide trifluoroacetate,(1S,3R)-5-amino-3-(5-(3-(5-(2,2-difluoroethoxy)pyrazin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide trifluoroacetate,(1S,3R)-5-amino-3-(5-(3-(5-chloropyrimidin-2-yl)isoxazol-5-yl)-2-fluorophenyl)-3,6,6-trimethyl-1-(methylimino)-3,6-dihydro-2H-1,4-thiazine1-oxide trifluoroacetate,(1S,3S)-3-[2-fluoro-5-[3-(5-methoxypyrazin-2-yl)isoxazol-5-yl]phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-aminetrifluoroacetate,(1S,3S)-3-[5-[3-(5-chloropyrimidin-2-yl)isoxazol-5-yl]-2-fluoro-phenyl]-3-(fluoromethyl)-6,6-dimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-5-aminetrifluoroacetate,2-[5-[3-[(1R,3R)-5-amino-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-3-yl]-4-fluoro-phenyl]isoxazol-3-yl]pyrimidine-5-carbonitriletrifluoroacetate, and6-[4-[3-[(1R,3R)-5-amino-3,6,6-trimethyl-1-methylimino-1-oxo-2H-1,4-thiazin-3-yl]-4-fluoro-phenyl]triazol-1-yl]pyridine-3-carbonitriletrifluoroacetate.
 24. A compound of formula I according to any of claims1-23 for use as therapeutically active substance.
 25. A compound offormula I according to claims 1-23 for the use as therapeutically activesubstance for the therapeutic and/or prophylactic treatment of diseasesand disorders characterized by elevated β-amyloid levels and/orβ-amyloid oligomers and/or β-amyloid plaques and further deposits orAlzheimer's disease.
 26. A pharmaceutical composition comprising acompound as described in any one of claims 1-23.
 27. The invention ashereinbefore described.